Medical delivery device with laminated stopper

ABSTRACT

The present disclosure relates to a medical delivery device that includes a barrel having an inner surface, a plunger rod having a distal end inserted within the barrel, and a stopper attached to the distal end of the plunger rod and contacting at least a portion of the inner surface of the barrel. In at least one embodiment, the inner surface is hydrophilic. The stopper may include an elastomeric body, one or more fluoropolymer layers, and two or more ribs laminated with the one or more fluoropolymer layers. In some embodiments, the contact width between at least one rib having a sealing surface and the portion of the inner surface of the barrel measured at a compressibility of greater than about 7.9% of the stopper is less than about 1.0 mm.

FIELD

The present invention relates to a medical delivery device with alaminated stopper, and in particular, to a medical delivery device witha stopper laminated with a fluoropolymer film.

BACKGROUND

Medical delivery devices such as syringes typically include a barrel, aplunger rod reciprocally movable in the barrel, and a stopper attachedto an end of the plunger rod. The stopper to be used for the syringe istypically air and liquid impermeable while also possessing low-frictionslidability. Air and liquid impermeability is important for eliminatingliquid leakage within the barrel and the introduction of air between anouter face of the stopper and an inner wall of the barrel when chargingor discharging the liquid inside the syringe. Low-friction slidabilityis important for facilitating the charging and discharging of the liquidinside the syringe. In addition to these requirements, a medicalsyringe, in particular, must not adversely affect any pharmaceuticalcomposition such as biopharmaceuticals that come in contact with thesyringe (e.g., a pre-filled syringe comprising a pharmaceuticalcomposition).

Stoppers for conventional syringes are commonly made of a rubbermaterial such as natural rubber, isoprene rubber or styrene-butadienerubber which may be vulcanized. Although this type of conventionalstopper has satisfactory air and liquid impermeability, it does not havegood low-friction slidability. Accordingly, silicone lubricants aretypically applied to both the outer face of the stopper and the innerwall of the barrel such that the stopper can slide within the barrel.However, syringes comprising silicone lubricants cannot be used forpharmaceutical composition and the like because the silicone lubricantcan cause inactivation or otherwise impact the efficacy of thesepharmaceutical compositions. Therefore, in order to maintain thestability of the pharmaceutical composition, stoppers laminated with afluoropolymer film have been used. Since the air and liquidimpermeability of stoppers may also have an impact on the quality andstability of the pharmaceutical compositions, the stoppers laminatedwith a fluoropolymer film are required to have high levels of air andliquid impermeability. However, when stoppers laminated with afluoropolymer film are used with a glass or resin syringe having ahydrophilic or lubricant free inner surface, the stoppers undesirablyexhibit poorer air and liquid impermeability than conventional,non-laminated rubber stoppers.

Another problem associated with some fluoropolymer laminates is itsability to maintain air and liquid impermeability while also possessinglow-friction slidability. For example, some fluoropolymer laminatesfunction inconsistently and can distort during insertion of the plungerrod into the barrel and/or during movement of the plunger rod within thebarrel, which can create leak paths for the liquid. Additionaldifficulties with some fluoropolymer laminates include poor airtightnessdue to a rough outer surface especially when manufactured as a skivedfilm.

Accordingly, the need exists for stoppers laminated with a fluoropolymerfilm that are capable of achieving sufficient contact with a hydrophilicor lubricant free inner surface of a barrel of a glass or resin syringeto achieve high levels of air and liquid impermeability while alsomaintaining acceptably low break loose and slide forces (i.e.,low-friction slidability) but not so much contact that the fluoropolymerfilm is distorted to create leak paths that decrease air and liquidimpermeability.

SUMMARY

One embodiment relates to a medical delivery device that includes abarrel, a plunger rod having a distal end inserted within the barrel, astopper attached to the distal end of the plunger rod and contacting atleast a portion of the inner surface of the barrel. The stopper has anelastomeric body, one or more fluoropolymer layers, and two or more ribslaminated with the one or more fluoropolymer layers. A contact widthbetween at least one of the two or more ribs having a sealing surfaceand a portion of the inner surface of the barrel measured at acompressibility of greater than about 7.9% of the stopper is less thanabout 1.0 mm. In at least one embodiment, the barrel has a hydrophilicinner surface. Optionally, the hydrophilic inner surface is bare glass(e.g., free or substantially free of silicone oil).

In some embodiments, the medical delivery device further includes asliding surface that is less than about 2.0 mm, which is calculatedbased on a sum of the contact widths between at least one of the two ormore ribs having a sealing surface and the portion of the inner surfaceof the barrel measured at a compressibility of greater than about 7.9%.

In some embodiments, at least one of: each rib of the two or more ribshaving a sealing surface includes a radius of curvature at an apex ofeach respective rib that is less than about 0.22 mm; and a ratio of amaximum outer diameter of all the ribs having a sealing surface to aninner diameter of the inner surface of the barrel is nominally greaterthan about 1.08.

In some embodiments, a maximum outer diameter of the ribs having asealing surface is greater than about 5.0 mm, an inner diameter of theinner surface of the barrel is nominally between about 4.65 and about11.85 mm, and a ratio of the maximum outer diameter of the ribs having asealing surface to an inner diameter of the inner surface of the barrelis greater than about 1.08.

In another embodiment, a plunger rod includes a distal end that isinsertable into a barrel and a stopper attached to the distal end. Inone or more embodiment, the barrel has a hydrophilic inner surface. Thestopper is configured to contact at least a portion of the inner surfaceof the barrel. The stopper includes an elastomeric body, one or morefluoropolymer layers, and two or more ribs laminated with the one ormore fluoropolymer layers. Each rib of the two or more ribs having asealing surface includes a radius of curvature at an apex of eachrespective rib that is less than about 0.22 mm, and a ratio of a maximumouter diameter of all the ribs having a sealing surface to an innerdiameter of the inner surface of the barrel is greater than about 1.08.The plunger rod may be configured such that when the plunger rod isinserted in the barrel having an inner diameter of an inner surface ofthe barrel, a contact width between at least one of the two or more ribshaving a sealing surface and the portion of the inner surface of thebarrel measured at a compressibility of greater than about 7.9% of thestopper is less than about 1.0 mm.

In yet another embodiment, a stopper that is insertable in a barrelhaving a hydrophilic inner surface comprises an elastomeric body, one ormore fluoropolymer layers, and two or more ribs. The at least one of thetwo or more ribs are laminated with the one or more fluoropolymer layersand configured to contact at least a portion of the inner surface of thebarrel. each rib of the two or more ribs having a sealing surfacecomprises a radius of curvature at an apex of each respective rib thatis less than 0.22 mm, and a ratio of a maximum outer diameter of all theribs having a sealing surface to an inner diameter of the inner surfaceof the barrel is greater than 1.08, and wherein the stopper isconfigured such that when the stopper is inserted in the barrel havingan inner diameter of an inner surface of the barrel, a contact widthbetween at least one of the two or more ribs having a sealing surfaceand the portion of the inner surface of the barrel measured at acompressibility of greater than 7.9% of the stopper is less than about1.0 mm.

Optionally, the one or more fluoropolymer layers described herein mayinclude a single layer of densified expanded polytetrafluoroethylene(ePTFE), or the one or more fluoropolymer layers may include a compositefluoropolymer film having a barrier layer and a porous layer, thebarrier layer including densified ePTFE, polytetrafluoroethylene (PTFE),fluorinated ethylene propylene (FEP), polyethylene, polypropylene,polyvinylidene fluoride, polyvinylfluoride, perfluoropropylevinylether,a perfluoroalkoxy polymer, and copolymers and combinations thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be better understood in view of the followingnon-limiting figures, in which:

FIG. 1 illustrates a partial cross sectional side view of a syringe inaccordance with some embodiments;

FIGS. 2-9 depict cross sectional side views of stoppers in accordancewith some embodiments;

FIG. 10A depicts a cross sectional side view of a non-compressed stopperin accordance with some embodiments; and

FIG. 10B depicts a cross sectional side view of a compressed stopper inaccordance with some embodiments.

DETAILED DESCRIPTION I. Introduction

Persons skilled in the art will readily appreciate that various aspectsof the present disclosure can be realized by any number of methods andapparatus configured to perform the intended functions. It should alsobe noted that the accompanying drawing figures referred to herein arenot necessarily drawn to scale, but may be exaggerated to illustratevarious aspects of the present disclosure, and in that regard, thefigures should not be construed as limiting.

The present disclosure is directed to a medical delivery device (e.g., asyringe), a plunger rod and a stopper laminated with a fluoropolymerfilm. The fluoropolymer laminate provides a low friction barrier betweenan elastomeric stopper and a pharmaceutical composition (e.g., a drug,medicine or other therapeutic) in the medical delivery device, and mayinhibit materials from leaching from the elastomeric stopper or fromextraction of compounds from the pharmaceutical composition by theelastomer. Fluoropolymer laminates have good biocompatibility, have goodmechanical integrity, are inert, and are processable.

In some embodiments, the stopper has a compressibility (C %) that isgreater than about 7.9%, between about 9.5 and about 20.0%, betweenabout 11.75 and about 18.5%, between about 14.0 and about 14.5. In oneexemplary embodiment, the compressibility may be about 14.4%. Inaddition, the stopper includes at least two ribs laminated with afluoropolymer layer. At least one rib with a sealing surface preferablyhas a contact width (w) measured at the compressibility (C %) of lessthan about 1.0 mm. In some embodiments, the contact width at thecompressibility is between about 0.05 mm and about 1.0 mm, between about0.1 and about 0.75 mm, or between about 0.2 and about 0.5 mm.

In some embodiments, the stopper also includes a sliding surface (S),which is a sum of the contact widths (w) of all the ribs having asealing surface. The sliding surface may be less than about 2.0 mm, orbetween about 0.05 mm and about 1.9 mm, between about 0.1 mm and about1.65 mm, or between about 0.5 mm and about 1.25 mm. Optionally, at leastone rib having a sealing surface has a predefined radius of curvature(r) at the apex of the rib of less than about 0.22 mm, between about0.05 and about 0.20 mm, or between about 0.12 and about 0.17 mm.Additionally or alternatively, the ratio of a maximum outer diameter (v)of at least one rib having a sealing surface to an inner diameter (y) ofthe inner surface of the barrel is greater than about 1.08, betweenabout 1.10 and about 1.25, or between about 1.13 and about 1.23.

In certain embodiments, the fluoropolymer layer may include afluoropolymer film, such as a polytetrafluoroethylene (PTFE) ordensified expanded polytetrafluoroethylene (ePTFE) film. Films based onPTFE or ePTFE can provide thin and strong barrier layers to leachablesand extractables. The superior strength of the expanded fluoropolymerstructure allows these materials to form thin barriers, which remainintact during the forming process and installation of the stopper intothe syringe barrel.

The use of at least partially porous and advantageously fibrilizingmaterials, such as ePTFE in combination with other materials, providesnumerous advantages. In one aspect, the use of such porous materials mayprovide a scaffold that enables thin strong barrier layers to be madeand improves the bond between the elastomer and the laminate. Laminatecompliance is beneficial to maintaining a seal between the stopper andthe barrel. Porous materials also provide for improved compliance of thestopper. Improved compliance may result from reduced film thickness,flexural compliance, and/or the compressibility of one or more layers ofthe porous material. Accordingly, by providing a laminate that is atleast partially porous to the outside (e.g. external or outermostsurface) of the stopper, the seal between the stopper and syringe barrelmay be improved while the sliding force is minimized.

The laminate may be of single layer or multiple layer construction. Asdescribed herein, layers may be described functionally. However, thefunctional names of the various layers in the descriptions ofembodiments that follow may not describe all of the potential functionsof any given layer. Accordingly, it will be understood that suchfunctional nomenclature is not intended to be limiting of any layerproperty. For example, a laminate layer may have additional propertiesand functions such as providing a low friction surface, increasing bondstrength and the like. Moreover, in multi-layer embodiments, each layermay contribute to the reduction of leachable and extractable materialsregardless of its designation as a barrier layer or otherwise.

II. Syringe

FIG. 1 depicts a syringe 10 (optionally a prefilled syringe) inaccordance with at least one embodiment. As the skilled artisan willappreciate, although the present invention is described hereafter as itrelates to a syringe, other types of medical delivery devices arecontemplated, such as, for example, an auto-injector or cartridge,without departing from the spirit and scope of the present disclosure.The syringe 10 includes a barrel 15 having opposed distal and proximalends 20 and 25 and a receiving chamber 30 positioned between the distaland proximal ends 20 and 25. The barrel 15 may be formed of asubstantially rigid or hard material, such as a glass material (e.g.,borosilicate glass), a ceramic material, one or more polymeric materials(e.g., polypropylene, polyethylene, and copolymers thereof), a metallicmaterial, or a plastic material (e.g., cyclic olefin polymers (COC) andcyclic olefin copolymers (COP), and combinations thereof.

In certain embodiments, the barrel 15 is formed of glass (e.g., bareglass, without any lubricants thereon), resin, plastic, metal, or likematerials and optionally has a hydrophilic interior wall characterizedby the absence of a lubricant such as, but not limited to, silicone orsilicone oil. As used herein, the term “hydrophilic interior wall”refers to a material (e.g., bare glass that is free or substantiallyfree of silicone oil) that has a contact angle of deionized water on aflat surface of the material of less than about 90°, which indicateshigh wettability.

The distal end 20 of barrel 15 includes an elongated tip 35 extendingthrough and communicating with the receiving chamber 30. In someembodiments, a cap 40 is disposed at the distal end 20 of the barrel 15.The cap 40 includes a proximal end 45 mated to the distal end 20 or tothe elongated tip 35 and a closed distal end 50. Thus, the cap 40inhibits or prevents ambient air from communicating with the receivingchamber 30 through the elongated tip 35. Optionally, a piercing element55 is also disposed at the distal end 20 of the barrel 15. The piercingelement 55 includes a proximal end 60 mated to the distal end 20 or tothe elongated tip 35 and a distal end 65. It is within the purview ofthe present disclosure that the piercing element 55 may include asharply pointed needle cannulae, or a blunt-ended cannulae, such asthose employed with “needleless” systems. For purposes of illustration,the piercing element 55 depicted and described herein is formed as asharply pointed, elongate needle cannula 55 including the proximal end60, a sharply pointed distal end 65 and a lumen 70 extending between theproximal end 60 and the distal end 65. Proximal end 60 of needle cannula55 may be rigidly mounted to the elongated tip 35 of the barrel 15.

In some embodiments, the cap 40 is mounted over needle cannula 55 and isreleasably engaged to the elongated tip 35 of the barrel 15. The cap 40may be formed from a rigid material such as plastic, or can be formedfrom a flexible material such as rubber, or from like materials orcombinations known to the skilled artisan. The cap 40 may be configuredfor closing the lumen 70 of the needle cannula 55 in fluid communicationwith a pharmaceutical composition, and/or to otherwise protectivelyseal, engage or surround sharply pointed distal end 65 of needle cannula55 and isolate same from the ambient environment. Thus, the cap 40prevents ambient air from communicating with the receiving chamber 30through needle cannula 55.

The proximal end 25 of barrel 15 may include a flange 80 to be used as afinger stopper for pressing and pulling a plunger rod 85 reciprocally inthe barrel 15. The plunger rod 85 has opposed distal and proximal ends90 and 95 with a stopper 100 attached to the distal end 90. Stopper 100includes opposed proximal and distal ends 105 and 110 and a side surface115 extending therebetween. The side surface 115 of stopper 100 mayinclude two or more ribs 120 such as one or more circumferentiallyextending annular ribs. The stopper 100 is preferably formed of anelastomeric body 125 and one or more laminate layers 130. Theelastomeric body 125 may include any suitable elastomer, and moreparticularly, rubbers constructed from butyl, bromobutyl, chlorobutyl,silicone, nitrile, styrene butadiene, polychloroprene, ethylenepropylene diene, fluoroelastomers, thermoplastic elastomers (TPE), andcombinations and blends thereof. In some embodiments, the elastomericbody 125 may have an initial modulus (small strain) of between about 2.5MPa to about 5 MPa, or between about 3 MPa to about 4 MPa. In onenon-limiting embodiment, the initial modulus may be, for example, about3.5 MPa (plus/minus measurement and variability tolerance). Thematerials of the one or more laminate layers 130 are chosen, asdescribed in detail herein, to provide a low coefficient of friction,compliance, low extractables and leachables, and good barrier propertiesas they relate to extractables and leachables from the elastomeric body125, as well as good air and liquid impermeability. For example, the oneor more laminate layers 130 may include one or more fluoropolymer films,such as, but not limited to PTFE or ePTFE films.

FIG. 1 also shows a material 135 provided in the receiving chamber 30 ofbarrel 15 (e.g., a prefilled syringe). For purposes of illustration butnot of limitation, the material 135 is herein identified as apredetermined dose of a pharmaceutical composition 135; however, itshould be understood that the material 135 could be any type of liquidor material capable of being expelled from a syringe, or the material135 may be all together absent from the receiving chamber (e.g., anunfilled syringe).

III. Laminate Layers

In some embodiments, the one or more laminate layers 130 may include asingle layer of a fluoropolymer. FIG. 2 depicts a stopper 100 thatincludes an elastomeric body 125 and a single layer of fluoropolymer orbarrier layer 140. Examples of elastomers that can be used to form theelastomeric body 125 include any elastomer suitable for the application,most notably rubbers constructed from butyl, bromobutyl, chlorobutyl,silicone, nitrile, styrene butadiene, polychloroprene, ethylenepropylene diene, fluoroelastomers, thermoplastic elastomers (TPE),thermoplastic vulcanizates (TPV), and materials sold under the tradename VITON®, and combinations and blends thereof. Exemplary elastomericmaterials include, but are not limited to, butyl rubber, bromobutylrubber, chlorobutyl rubber, silicone, nitrile, styrene butadiene,polychloroprene, ethylene propylene diene, fluoroelastomers andcombinations thereof.

Examples of fluoropolymers that can be used to form the fluoropolymer orbarrier layer 140 include any fluoropolymer suitable for theapplication, most notably a densified expanded fluoropolymer,polytetrafluoroethylene (PTFE), densified ePTFE, fluorinated propylene(FEP), polyethylene, polypropylene, polyvinylidene fluoride,polyvinylfluoride, perfluoropropylevinylether, perfluoroalkoxy polymers,tetrafluoroethylene (TFE), and copolymers and combinations thereof. Thebarrier film may also include a composite fluoropolymer film having abarrier layer and a porous layer. The porous layer, for example, maybeformed of ePTFE or other porous expanded and fibrilizing fluoropolymers(for example, ePTFE as taught in U.S. Pat. No. 6,541,589). The ePTFElayers may be filled with an organic or inorganic material to providecolor, lubricity, or other function.

In a some embodiments, the fluoropolymer or barrier layer 140 mayinclude a densified expanded fluoropolymer, preferably a densifiedexpanded polytetrafluoroethylene (ePTFE). A densified ePTFE film may beprepared in the manner described in U.S. Pat. No. 7,521,010 to Kennedy,et al., U.S. Pat. No. 6,030,694 to Dolan et al., U.S. Pat. No. 5,792,525to Fuhr et al., or U.S. Pat. No. 5,374,473 to Knox et al., Expandedcopolymers of PTFE, such as are described in U.S. Pat. No. 5,708,044 toBranca, U.S. Pat. No. 6,541,589 to Baillie, U.S. Pat. No. 7,531,611 toSabol et al., U.S. Pat. No. 8,637,144 to Ford, and U.S. Pat. No.9,139,669 to Xu et al. may be utilized if they are densified.

The barrier film may also include an expanded polymeric materialincluding a functional tetrafluoroethylene (TFE) copolymer materialhaving a microstructure characterized by nodes interconnected byfibrils, where the functional TFE copolymer material includes afunctional copolymer of TFE and PSVE (perfluorosulfonyl vinyl ether), orTFE with another suitable functional monomer, such as, but not limitedto, vinylidene fluoride (VDF), vinyl acetate, or vinyl alcohol. Thefunctional TFE copolymer material may be prepared, for example,according to the methods described in U.S. Pat. No. 9,139,669 to Xu etal. or U.S. Pat. No. 8,658,707 to Xu et al.

The densified ePTFE film may be combined with an elastomer to constructthe stopper 100. In this embodiment, the densified ePTFE film isthermoformed to make a preform. Thermoforming is done at processtemperatures sufficiently above the nodal melt temperature to ensuremelt forming while preserving barrier and strength properties. The highstrength of the resulting expanded film allows for forming extremelythin films. The films can be made with thicknesses ranging from about0.5 micron to about 20 microns. In some embodiments, the films have athickness that is less than about 30 microns. The film can optionally bepre-treated or post-treated with chemical etching, plasma treating,corona, roughening, or the like to improve bonding to the elastomericbody 125. The thermoformed, densified ePTFE preform can be combined withthe elastomeric body 125 by injection molding, compression molding,priming and post laminating around an elastomer perform, or by othersuitable methods known to those of skill in the art.

In another embodiment, as shown in FIG. 3, the one or more laminatelayers 130 may include a composite fluoropolymer film having a barrierlayer 145 and a porous layer 150. The barrier layer 145 can include afluoropolymer such as a densified expanded fluoropolymer, PTFE, ePTFE,densified ePTFE, FEP, polyethylene, polypropylene, polyvinylidenefluoride, polyvinylfluoride, perfluoropropylevinylether, perfluoroalkoxypolymers, TFE, and copolymers and combinations thereof. The porous layer150 may include ePTFE (for example, ePTFE as taught in U.S. Pat. No.6,541,589 to Bailie) or other porous expanded and fibrilizingfluoropolymers. The one or more laminate layers 130 having the barrierlayer 145 and the porous layer 150 may be constructed by coating orotherwise depositing the fluoropolymer onto the porous layer to createthe composite fluoropolymer film. One such example of this would be todeposit granular or powdered fluoropolymers such as powdered PTFE onto aporous ePTFE surface in a coating process. The ePTFE support should beconstructed to be thermally stable enough to allow heat treatment of thedeposited fluoropolymer for the creation of a barrier or for bonding ofthe deposited layer to the porous ePTFE support. The ePTFE layer may befilled with an organic or inorganic material to provide color,lubricity, or other functional attributes.

In accordance with some aspects of the present invention, the elastomermaterial of the elastomeric body 125 may at least partially penetratethe porous layer 150. FIG. 4 illustrates a cross-section of a stopperdepicting the barrier layer 145, the porous layer 150, and theelastomeric body 125. Specifically, FIG. 4 shows a region of partialpenetration 160 of the elastomer material of the elastomeric body 125into the porous layer 150. Penetration of the elastomer material of theelastomeric body 125 into the porous layer 150 may improve the bondbetween the elastomeric body 125 and the one or more laminate layers130.

In accordance with other aspects, the material of the barrier layer 145may at least partially penetrate the porous layer 150. FIG. 5illustrates a cross-section of a stopper depicting the barrier layer145, the porous layer 150, and the elastomeric body 125. Specifically,FIG. 5 shows a region of partial penetration 165 of the material of thebarrier layer 145 into the porous layer 150. Penetration of the materialof the barrier layer 145 into the porous layer 150 may improve the bondbetween the barrier layer 145 and the porous layer 150. The region ofpartial penetration 165 may also provide support for the barrier layer145 to impart strength, toughness, compliance and stability, which maybe beneficial in both the forming process and in the application.

In another embodiment, as shown in FIG. 6, the one or more laminatelayers 130 may comprise a composite fluoropolymer film having adensified expanded fluoropolymer layer 170, a barrier melt fluoropolymerlayer 175, and a porous layer 180. The densified expanded fluoropolymerlayer 170 can may include or be formed of a densified ePTFE. The barriermelt fluoropolymer layer 175 may include a fluoropolymer such as adensified expanded fluoropolymer, PTFE, ePTFE, densified ePTFE, orfluorinated propylene (FEP), polyethylene, polypropylene, polyvinylidenefluoride, polyvinylfluoride, perfluoropropylevinylether, perfluoroalkoxypolymers, and copolymers and combinations thereof. The porous layer 150may include or be formed of ePTFE or other porous expanded andfibrilizing fluoropolymers. The one or more laminate layers 130 havingthe densified expanded fluoropolymer layer 170, the barrier meltfluoropolymer layer 175 and the porous layer 180 may be constructed bycoating or otherwise depositing the fluoropolymer onto the porous layerto create the composite fluoropolymer film. The densified ePTFE film,fluoropolymer, and porous layer may be thermoformed to make a preform,and may be combined with the elastomeric body 125 by injection molding,compression molding, priming and post laminating around an elastomerperform, or other suitable methods known to the skilled artisan.

In accordance with some aspects, the elastomer material of theelastomeric body 125 may at least partially penetrate the porous layer180. FIG. 7 shows a cross-section of a stopper depicting a densifiedexpanded fluoropolymer layer 170, a barrier melt fluoropolymer layer175, and a porous layer 180. Specifically, FIG. 7 shows a region ofpartial penetration 185 of the elastomer material of the elastomericbody 125 into the porous layer 180. Penetration of the elastomermaterial of the elastomeric body 125 into the porous layer 180 mayimprove the bond between the elastomeric body 125 and the one or morelaminate layers 130.

In accordance with other aspects, the material of the barrier meltfluoropolymer layer 175 may at least partially penetrate the porouslayer 180. FIG. 8 shows a cross-section of a stopper according to anembodiment depicting densified expanded fluoropolymer layer 170, abarrier melt fluoropolymer layer 175 and a porous layer 180.Specifically, FIG. 8 shows a region of partial penetration 190 of thematerial of the barrier melt fluoropolymer layer 175 into the porouslayer 180. Penetration of the material of the barrier melt fluoropolymerlayer 175 into the porous layer 180 may improve the bond between thebarrier melt fluoropolymer layer 175 and the porous layer 180. Theregion of partial penetration 190 may also provide support for thebarrier melt fluoropolymer layer 175 to impart strength, toughness,compliance and stability, which is beneficial in both the formingprocess and in use.

In accordance with some aspects, the material of the barrier meltfluoropolymer layer 175 may at least partially penetrate the densifiedexpanded fluoropolymer layer 170. FIG. 9 shows a cross-section of astopper depicting a densified expanded fluoropolymer layer 170, abarrier melt fluoropolymer layer 175, and a porous layer 180.Specifically, FIG. 9 shows a region of partial penetration 195 of thematerial of the barrier melt fluoropolymer layer 175 into the densifiedexpanded fluoropolymer layer 170. Penetration of the material of thebarrier melt fluoropolymer layer 175 into the densified expandedfluoropolymer layer 170 may improve the bond between the barrier meltfluoropolymer layer 175 and the densified expanded fluoropolymer layer170. The region of partial penetration 195 may also provide support forthe barrier melt fluoropolymer layer 175 to impart strength, toughness,compliance and stability, which is beneficial in both the formingprocess and in use.

The stopper 100 may include various degrees of penetration of either theelastomer material or the barrier polymer into the porous material orthe densified expanded fluoropolymer layer as shown in FIGS. 4, 5, and7-9, and as described in U.S. Pat. No. 8,722,178 to Ashmead, et al.,U.S. Patent Publication No. 2012/0251748 to Ashmead, et al., and U.S.Patent Publication No. 2016/0022918 to Ashmead, et al.. It is to beappreciated that there are many variations of the processes describedherein that could be utilized for forming the stopper 100 withoutdeparting from the scope and/or spirit the invention. Some of thesevariations may include, but are not limited to, forming any of thefluoropolymers used in the stopper 100 of the present invention with anexpanded fluoropolymer film based on PTFE, modified PTFE, and PTFE andTFE copolymers such as, for example, the resins as described in U.S.Pat. No. 6,541,589 to Bailie and U.S. Pat. No. 8,637,144 to Ford.

IV. Stopper Structure

In some embodiments, the stopper 100 is configured to achieve containerclosure integrity with high levels of air and liquid impermeabilitywhile also maintaining acceptably low break loose and slide forces.FIGS. 10A and 10B show such a stopper 100 that includes a body 205having opposed proximal and distal ends 210 and 215 and two or more ribs220. A head portion 225 is formed integrally with the distal end 215 ofthe body 205. One or more annular grooves 230 is formed in an outersurface of the body 205, thus forming and connecting the two or moreribs 220. At least one of the two or more ribs 220 is laminated with theone or more laminate layers 130. A cavity 240 may extend from theproximal end of 210 of the body 205 towards the distal end 215. Thedistal end 90 of the plunger rod 85 may be inserted and fixed inside thecavity 240 of the stopper.

The two or more ribs 220 can be classified based on whether they have asealing surface or a non-sealing surface. As used herein, the term“sealing surface” refers to a rib having a compressibility of greaterthan about 7.9%, and the term “non-sealing surface” refers to a ribhaving a compressibility of about 7.9% or less. For example, the tworibs shown in FIGS. 10A and 10B as being the furthest towards the distalend 215 of the body 205 have a compressibility of greater than about7.9%, and thus are referred to as having a sealing surface. In contrast,the one rib shown in FIGS. 10A and 10B as being the furthest towards theproximal end 210 of the body 205 has a compressibility of about 7.9% orless, and thus is referred to as having a non-sealing surface. As theskilled artisan will appreciate, although the present invention isdescribed hereafter as it relates to rib arrangement shown in FIGS. 10Aand 10B, other types of rib arrangements are contemplated, such as, forexample having three ribs with sealing surfaces, without departing fromthe spirit and scope of the present disclosure.

Each rib 220 having a sealing surface includes at least one a predefinedouter diameter (x) measured from an apex of the respective rib with thestopper 100 in a non-compressed state (see, e.g., FIG. 10A), a curvature(c) having a predefined radius of curvature (r) at the apex of therespective rib that is measured with the stopper 100 in a non-compressedstate (see, e.g., FIG. 10A), and a contact width (w) between eachrespective rib and an inner surface 240 of the barrel measured at acompressibility (C %) of the stopper 100 in a compressed state (see,e.g., FIG. 10B). In some embodiments, at least one of: the predefinedouter diameter (x) of at least one rib 220 having a sealing surface isgreater than about 5.0 mm, between about 5.0 mm and about 14.0 mm, orbetween about 5.5 mm and about 10 mm. In some embodiments, thepredefined outer diameter (x) may be, for example, about 7.42 mm orabout 5.5 mm. The predefined radius of curvature (r) of at least one rib220 having a sealing surface is less than about 0.22 mm, between about0.05 mm and about 0.20 mm, or between about 0.12 mm and about 0.17 mm.The contact width (w) of at least one rib 220 having a sealing surfacemeasured at the compressibility (C %) is less than about 1.0 mm. In someembodiments, the contact width at the compressibility is between about0.05 mm and about 1.0 mm, between about 0.1 and about 0.75 mm, orbetween about 0.2 and about 0.5 mm. A sliding surface (S) of the stopper100 includes a sum of the contact widths (w) of all the ribs having asealing surface that is less than 2.0 mm. The sliding surface may beless than about 2.0 mm, or between about 0.05 mm and about 1.9 mm,between about 0.1 mm and about 1.65 mm, or between about 0.5 mm andabout 1.25 mm.

As the skilled artisan will appreciate, the ribs 220 can be structuredin any number of configurations, and FIGS. 10A and 10B are provided forpurposes of illustration only, and are not intended to limit the presentdisclosure. For example, in certain embodiments, all of the ribs 220having a sealing surface may have a same predefined outer diameter (x).In other embodiments, each rib 220 having a sealing surface may have itsown predefined outer diameter (x). For example, a distal or leading ribmay have a predefined outer diameter (1 x) and a proximal or trailingrib may have a predefined outer diameter (2 x) that is between about 75%and about 99.9% of the predefined outer diameter (1 x).

The compressibility (C %) is defined in relation to a maximum outerdiameter (v) of the ribs 220 having a sealing surface of the stopper 100in a non-compressed state and the inner diameter (y) of the innersurface 240 of the barrel as follows: C %=((v−y)/v)×100. For example,understanding that each of the ribs 220 having a sealing surface mayhave its own predefined outer diameter (x), and thus its owncompression, compressibility (C %) of the stopper 100 is defined inrelation to the largest outer diameter (x) (i.e., the maximum outerdiameter (v)) out of all of the ribs 220 having a sealing surface of thestopper 100 in a non-compressed state. In some embodiments, the maximumouter diameter (v) of the ribs 220 having a sealing surface is greaterthan about 5.0 mm, between about 5.0 mm and about 14.0 mm, or betweenabout 5.5 mm and about 10 mm. In some embodiments, the sealing surfacemay be, for example, about 7.42 mm or about 5.5 mm; the inner diameter(y) may be between about 2.5 mm and about 30.0 mm, between about 4.5 mmand about 20.0 mm, or between about 5.5 mm and about 11.5 mm. In someembodiment, the inner diameter may be, for example, about 6.35 mm ornominally (a tolerance of +/−0.1 on the 4.65 side and a tolerance of+/−0.2 on the 11.85) between about 4.65 mm and about 11.85 mm; and thecompressibility (C %) of the stopper may be greater than about 7.9%,between about 9.5% and about 20.0%, or between about 11.75% and about18.5%. In some embodiments, the compressibility may be, for example,about 14.4%. In some embodiments, a ratio of the maximum outer diameter(v) of the ribs 220 having a sealing surface to the inner diameter (y)of the inner surface 240 of the barrel may be greater than, for example,about 1.08, or between about 1.10 and about 1.25, or between about 1.13and about 1.23.

In some embodiments, the stopper 100 may be configured based on theaforementioned composition of the one or more laminate layers 130 andproperties of the two or more ribs 220 to have a predetermined slideforce and predetermined seal pressure. In some embodiments, thepredetermined slide force is a peak extrusion force of less than about20 N at speeds of 50-250 mm/min using a syringe filled with water. Insome embodiments, the predetermined seal pressure is a seal pressureadequate to achieve a helium leak rate of less than 6×10⁻⁶ sccs.

Referring to FIGS. 10A and 10B, it was found that the seal pressure of astopper laminated with a fluoropolymer film that is in contact with ahydrophilic or lubricant free inner surface of a barrel dependsparticularly upon compressibility (C %), and the break loose (e.g., theamount of force required to begin moving the stopper from a stationaryposition within the barrel) and slide forces (e.g., the amount of forcerequired to move the stopper parallel along the inner surface of thebarrel) particularly depend upon the contact width (w) or slidingsurface (S). Additionally, it was found that distortion of thefluoropolymer film (both the portion of the fluoropolymer filmcontacting the inner surface of the barrel and the portion of thefluoropolymer film not contacting the inner surface of the barrel) ofthe stopper that is in contact with a hydrophilic or lubricant freeinner surface of a barrel depends particularly upon the dimensions ofthe two or more ribs. Some of the conventional stoppers laminated with afluoropolymer film when compressed enough to achieve a desired sealpressure have unacceptable break loose and slide forces due to excessivecontact area or sliding surface between the stopper and the innersurface of barrel. Moreover, some conventional laminates tends todistort during movement of the plunger rod within the barrel duringcharging or discharging due to the structure of the one or more annulargrooves and the two or more ribs.

However, it has been surprisingly and unexpectedly found that when thecontact width (w) of at least one rib with a sealing surface measured ata compressibility (C %) of greater than 7.9% is less than about 1.0 mm,or between about 0.05 mm and about 1.0 mm, between about 0.1 and about0.75 mm, or between about 0.2 mm and about 0.5 mm and a sliding surface(S) of the stopper 100 that includes a sum of the contact widths (w) ofall the ribs having a sealing surface is less than about 2.0 mm, orbetween about 0.05 mm and about 1.9 mm, between about 0.1 mm and about1.65 mm, or between about 0.5 and about 1.25 mm, the stoppers of thepresent disclosure achieve a desired seal pressure with acceptable breakloose and slide forces. Moreover, it has been surprisingly andunexpectedly found that when the predefined radius of curvature (r) ofat least one rib having a sealing surface is at less than about 0.22 mm,or between about 0.05 and about 0.20 mm, or between about 0.12 and about0.17 mm, and the ratio of the maximum outer diameter (v) of at least onerib having a sealing surface to the inner diameter (y) of the innersurface of the barrel is greater than about 1.08, between about 1.10 andabout 1.25, or between about 1.13 and about 1.23, the fluoropolymerlaminate of the stoppers do not distort under the compressibility (C %),which is necessary to achieve an adequate seal pressure while allowingfor acceptably low break loose and slide forces.

Additionally, it has been surprisingly and unexpectedly found that usingthe aforementioned one or more laminate layers allows for improvedgeometry with respect to aforementioned properties of the two or moreribs without causing leak paths. Accordingly, the aforementioned aspectsof the present invention allow for the construction of stopperslaminated with a fluoropolymer film that achieve sufficient contact withthe inner surface of the barrel of a glass or resin syringe (hydrophilicand/or lubricant free) to achieve high levels of air and liquidimpermeability while also maintaining acceptably low break loose andslide forces (i.e., low-friction slidability) but not so much contactthat the fluoropolymer film surface is distorted to create leak pathsthat decrease the air and liquid impermeability.

In another aspect, the medical delivery device, plunger rod, and stopperdescribed herein may be used in combination different therapeuticcompounds such as, for example, drugs and biologics, including but notlimited to, antibodies, antisense, RNA interference, gene therapy,primary and embryonic stem cells, vaccines, and combinations thereof.For instance, the embodiments described herein may be utilized incombination with any or all of the following:

Cell therapy using cells that are derived primarily from endoderm suchas Exocrine secretory epithelial cells and Hormone-secreting cells;ectoderm such as Keratinizing epithelial cells, Wet stratified barrierepithelial cells, Sensory transducer cells, Autonomic neuron cells,Sense organ and peripheral neuron supporting cells, Central nervoussystem neurons and glial cells, Lens cells; mesoderm such as Metabolismand storage cells, Barrier function cells (lung, gut, exocrine glands,and urogenital tract), Extracellular matrix cells, Contractile cells,Blood and immune system cells, Germ cells, Nurse cell, Interstitialcells or a combination thereof. Additionally cells that are genetically,chemically or physically altered or modified are considered to be in thescope of the invention.

Examples of Exocrine secretory epithelial cells include, but are notlimited to, Salivary gland mucous cell, Salivary gland number 1, VonEbner's gland cell in tongue, Mammary gland cell, Lacrimal gland cell,Ceruminous gland cell in ear, Eccrine sweat gland dark cell, Eccrinesweat gland clear cell, Apocrine sweat gland cell, Gland of Moll cell ineyelid, Sebaceous gland cell, Bowman's gland cell in nose, Brunner'sgland cell in duodenum, Seminal vesicle cell, Prostate gland cell,Bulbourethral gland cell, Bartholin's gland cell, Gland of Littre cell,Uterus endometrium cell, Isolated goblet cell of respiratory anddigestive tracts, Stomach lining mucous cell, Gastric gland zymogeniccell, Gastric gland oxyntic cell, Pancreatic acinar cell, Paneth cell ofsmall intestine, Type II pneumocyte of lung, Clara cell of lung;Hormone-secreting cells including but not limited to: Anterior pituitarycells, Intermediate pituitary cell, Magnocellular neurosecretory cells,Gut and respiratory tract cells, Thyroid gland cells, Parathyroid glandcells, Adrenal gland cells, Leydig cell of testes secretingtestosterone, Theca interna cell of ovarian follicle secreting estrogen,Corpus luteum cell of ruptured ovarian follicle secreting progesterone,Juxtaglomerular cell, Macula densa cell of kidney, Peripolar cell ofkidney, Mesangial cell of kidney, Pancreatic islets; Keratinizingepithelial cells including but not limited to: Epidermal keratinocyte,Epidermal basal cell, Keratinocyte of fingernails and toenails, Nail bedbasal cell, Medullary hair shaft cell, Cortical hair shaft cell,Cuticular hair shaft cell, Cuticular hair root sheath cell, Hair rootsheath cell of Huxley's layer, Hair root sheath cell of Henle's layer,External hair root sheath cell, Hair matrix cell; Wet stratified barrierepithelial cells including but not limited to: Surface epithelial cellof stratified squamous epithelium and basal cell of epithelia of cornea,tongue, oral cavity, esophagus, anal canal, distal urethra and vagina,Urinary epithelium cell; Sensory transducer cells including but notlimited to: Auditory inner hair cell of organ of Corti, Auditory outerhair cell of organ of Corti, Basal cell of olfactory epithelium,Cold-sensitive primary sensory neurons, Heat-sensitive primary sensoryneurons, Merkel cell of epidermis, Olfactory receptor neuron,Pain-sensitive primary sensory neurons, Photoreceptor cells of retina ineye: Proprioceptive primary sensory neurons, Touch-sensitive primarysensory neurons, Type I carotid body cell, Type II carotid body cell,Type I hair cell of vestibular system of ear, Type II hair cell ofvestibular system of ear, Type I taste bud cell; Autonomic neuron cellsincluding but not limited to: Cholinergic neural cell, Adrenergic neuralcell, Peptidergic neural cell; Sense organ and peripheral neuronsupporting cells including but not limited to: Inner pillar cell oforgan of Corti, Outer pillar cell of organ of Corti, Inner phalangealcell of organ of Corti, Outer phalangeal cell of organ of Corti, Bordercell of organ of Corti, Hensen cell of organ of Corti, Vestibularapparatus supporting cell, Taste bud supporting cell, Olfactoryepithelium supporting cell, Schwann cell, Satellite glial cell, Entericglial cell; Central nervous system neurons and glial cells including butnot limited to: Astrocyte, Neuron cells, Oligodendrocyte, Spindleneuron; Lens cells including but not limited to: Anterior lensepithelial cell, Crystallin-containing lens fiber cell; Metabolism andstorage cells including but not limited to: Adipocytes: Liver lipocyte;Barrier function cells including but not limited to: Kidney parietalcell, Kidney glomerulus podocyte, Kidney proximal tubule brush bordercell, Loop of Henle thin segment cell, Kidney distal tubule cell, Kidneycollecting duct cell, Principal cells, Intercalated cells, Type Ipneumocyte, Pancreatic duct cell, Nonstriated duct cell, Principal cell,Intercalated cell, Duct cell, Intestinal brush border cell, Exocrinegland striated duct cell, Gall bladder epithelial cell, Ductulusefferens nonciliated cell, Epididymal principal cell, Epididymal basalcell; Extracellular matrix cells including but not limited to:Ameloblast epithelial cell, Planum semilunatum epithelial cell ofvestibular system of ear, Organ of Corti interdental epithelial cell,Loose connective tissue fibroblasts, Corneal fibroblasts, Tendonfibroblasts, Bone marrow reticular tissue fibroblasts, Othernonepithelial fibroblasts, Pericyte, Nucleus pulposus cell ofintervertebral disc, Cementoblast/cementocyte, Odontoblast/odontocyte,Hyaline cartilage chondrocyte, Fibrocartilage chondrocyte, Elasticcartilage chondrocyte, Osteoblast/osteocyte, Osteoprogenitor cell,Hyalocyte of vitreous body of eye, Stellate cell of perilymphatic spaceof ear, Hepatic stellate cell, Pancreatic stelle cell; Contractile cellsincluding but not limited to: Skeletal muscle cell, Satellite cell,Heart muscle cells, Smooth muscle cell, Myoepithelial cell of iris,Myoepithelial cell of exocrine glands; Blood and immune system cellsincluding but not limited to: Erythrocyte, Megakaryocyte, Monocyte,Connective tissue macrophage, Epidermal Langerhans cell, Osteoclast,Dendritic cell, Microglial cell, Neutrophil granulocyte, Eosinophilgranulocyte, Basophil granulocyte, Hybridoma cell, Mast cell, Helper Tcell, Suppressor T cell, Cytotoxic T cell, Natural Killer T cell, Bcell, Natural killer cell, Reticulocyte, Stem cells and committedprogenitors for the blood and immune system; Germ cells including butnot limited to: Oogonium/Oocyte, Spermatid, Spermatocyte, Spermatogoniumcell, Spermatozoon; Nurse cell including but not limited to: Ovarianfollicle cell, Sertoli cell, Thymus epithelial cell; Interstitial cellsincluding but not limited to: Interstitial kidney cells and acombination thereof.

Examples of antibodies, antisense, RNA interference, or gene therapymade to protein targets or gene(s) of: Ataxia Telangiectasia Mutated,Tumor Protein p53, Checkpoint kinase 2, breast cancer susceptibilityprotein, Double-strand break repair protein, DNA repair protein RAD50,Nibrin, p53-binding protein, Mediator of DNA damage checkpoint protein,H2A histone family member X, Microcephalin, C-terminal-binding protein1, Structural maintenance of chromosomes protein 1A; Esterases;Phosphatases; Examples of Ion channels include but are not limited to:ligand-gated ion channels, voltage-gated ion channels; Examples ofgrowth factors include but are not limited to: nerve growth factor(NGF), vascular endothelial growth factor (VEGF), platelet-derivedgrowth factor (PDGF), C-fos-induced growth factor (FIGF),platelet-activating factor (PAF), transforming growth factor beta(TGF-β), b, one morphogenetic proteins (BMPs), Activin, inhibin,fibroblast growth factors (FGFs), granulocyte-colony stimulating factor(G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF),glial cell line-derived neurotrophic factor (GDNF), growthdifferentiation factor-9 (GDF9), epidermal growth factor (EGF),transforming growth factor-α (TGF-α), growth factor (KGF),migration-stimulating factor (MSF), hepatocyte growth factor-likeprotein (HGFLP), hepatocyte growth factor (HGF), hepatoma-derived growthfactor (HDGF), Insulin-like growth factors; Examples of GProtein-Coupled Receptors (GPCR) include but are not limited to:Adenosine receptor family, Adrenergic receptor family, Angiotensin IIreceptor, Apelin receptor, Vasopressin receptor family, Brain-specificangiogenesis inhibitor family, Bradykinin receptor family, Bombesinreceptor family, Complement component 3a receptor 1, Complementcomponent 5a receptor 1, Calcitonin receptor family, Calcitoninreceptor-like family, Calcium-sensing receptor, Cholecystokinin Areceptor (CCK1), Cholecystokinin B receptor (CCK2), Chemokine (C-Cmotif) receptor family, Sphingosine 1-phosphate receptor family,Succinic receptor, Cholinergic receptor family. Chemokine-like receptorfamily, Cannabinoid receptor family, Corticotropin releasing hormonereceptor family, prostaglandin D2 receptor, Chemokine C-X3-C receptorfamily, Chemokine (C-X-C motif) receptor family, Burkitt lymphomareceptor, Chemokine (C-X-C motif) receptor family, Cysteinyl leukotrienereceptor 2 (CYSLT2), chemokine receptor (FY), Dopamine receptor family,G protein-coupled receptor 183 (GPR183), Lysophosphatidic acid receptorfamily, Endothelin receptor family, Coagulation factor II (thrombin)receptor family, Free fatty acid receptor family, Formylpeptide receptorfamily, Follicle stimulating hormone receptor (FSHR), gamma-aminobutyricacid (GABA) B receptor, Galanin receptor family, Glucagon receptor,Growth hormone releasing hormone receptor (GHRH), Ghrelin receptor(ghrelin), Growth hormone secretagogue receptor 1b (GHSR1b), Gastricinhibitory polypeptide receptor (GIP), Glucagon-like peptide receptorfamily, Gonadotropin-releasing hormone receptor (GnRH), pyroglutamylatedRFamide peptide receptor (QRFPR), G protein-coupled bile acid receptor 1(GPBA), Hydroxycarboxylic acid receptor family, Lysophosphatidic acidreceptor 4 (LPA4) Lysophosphatidic acid receptor 5 (GPR92), Gprotein-coupled receptor 79 pseudogene (GPR79), Hydroxycarboxylic acidreceptor 1 (HCA1), G-protein coupled receptor (C5L2, FFA4, FFA4, FFA4,GPER, GPR1, GPR101, GPR107, GPR119, GPR12, GPR123, GPR132, GPR135,GPR139, GPR141, GPR142, GPR143, GPR146, GPR148, GPR149, GPR15, GPR150,GPR151, GPR152, GPR157, GPR161, GPR162, GPR17, GPR171, GPR173, GPR176,GPR18, GPR182, GPR20, GPR22, GPR25, GPR26, GPR27, GPR3, GPR31, GPR32,GPR35, GPR37L1, GPR39, GPR4, GPR45, GPR50, GPR52, GPR55, GPR6, GPR61,GPR65, GPR75, GPR78, GPR83, GPR84, GPR85, GPR88, GPR97, TM7SF1),Metabotropic glutamate receptor family, Gastrin releasing peptidereceptor (BB2), Orexin receptor family, Histamine receptor family,5-hydroxytryptamine receptor family, KISS1-derived peptide receptor(kisspeptin), Leucine-rich repeat-containing G protein-coupled receptorfamily, horiogonadotropin receptor (LH), Leukotriene B4 receptor (BLT1),Adenylate Cyclase Activating Polypeptide 1 Receptor 1 (mPAC1), Motilinreceptor, Melanocortin receptor family, Melanin concentrating hormonereceptor 1 (MCH1), Neuropeptide Y1 receptor (Y1), Neuropeptide Y2receptor (NPY2R), Opioid receptor family, Oxytocin recepter (OT), P2YPurinoceptor 12 (mP2Y12), P2Y Purinoceptor 6 (P2Y6), Pancreaticpolypeptide receptor family, Platelet-activating factor receptor family,Prostaglandin E receptor family, Prostanoid IP1 receptor (IP1),MAS-related GPR, member family, Rhodopsin (Rhodopsin), Relaxin familypeptide receptor family, Somatostatin receptor family, Tachykininreceptor family, Melatonin receptor family, Urotensin receptor family,Vasoactive intestinal peptide receptor 1 (mVPAC1), Neuromedin B Receptor(BB1), Neuromedin U receptor 1 (NMU1), Neuropeptides B/W receptorfamily, Neuropeptide FF receptor 1 (NPFF1), neuropeptide S receptor 1(NPS receptor), Neuropeptide Y receptor family, Neurotensin receptor 1(NTS1), Opsin 5 (OPN5), Opioid receptor-like receptor (NOP),Oxoeicosanoid (OXE) receptor 1 (OXE), Oxoglutarate (alpha-ketoglutarate)receptor 1 (OXGR1), Purinergic receptor family, Pyrimidinergic receptorfamily, Prolactin releasing hormone receptor (PRRP), Prokineticinreceptor family, Platelet activating receptor (PAF), Prostaglandin Freceptor family, Prostaglandin 12 (prostacyclin) receptor family,Parathyroid hormone receptor family, muscarinic 4 (rM4), Prostanoid DP2receptor (rGPR44), Prokineticin receptor family, Relaxin family peptidereceptor family, Secretin receptor (secretin), Smoothened, Frizzledclass receptor (Smoothened), trace amine associated receptor family,Tachykinin family, Thromboxane A2 receptor (TP), Thyrotropin-releasinghormone receptor (TRH1), Thyroid Stimulating Hormone Receptor (TSH);Examples of Protein kinases include but are not limited to: AP2associated kinase, Homo sapiens ABL proto-oncogene 1-non-receptortyrosine-protein kinase family, c-abl oncogene 1 receptor tyrosinekinase family, v-abl Abelson murine leukemia viral oncogene homolog 2,activin A receptor family, chaperone-ABC1 activity of bc1 complexhomolog (S. pombe) (ADCK3), aarF domain containing kinase 4 (ADCK4),v-akt murine thymoma viral oncogene homolog family, anaplastic lymphomareceptor tyrosine kinase family, protein kinase A family, protein kinaseB family, ankyrin repeat and kinase domain containing 1 (ANKK1), NUAKfamily-SNF1-like kinase, mitogen-activated protein kinase kinase kinasefamily aurora kinase A (AURKA), aurora kinase B (AURKB), aurora kinase C(AURKC), AXL receptor tyrosine kinase (AXL), BMP2 inducible kinase(BIKE), B lymphoid tyrosine kinase (BLK), bone morphogenetic proteinreceptor family, BMX non-receptor tyrosine kinase (BMX), v-raf murinesarcoma viral oncogene homolog B1 (BRAF), protein tyrosine kinase 6(BRK), BR serine/threonine kinase family, Bruton agammaglobulinemiatyrosine kinase (BTK), calcium/calmodulin-dependent protein kinasefamily, cyclin-dependent kinase family, cyclin-dependent kinase-likefamily, CHK1 checkpoint homolog (S. pombe) (CHEK1), CHK2 checkpointhomolog (S. pombe) (CHEK2), Insulin receptor, isoform A (INSR), Insulinreceptor, isoform B (INSR), rho-interacting serine/threonine kinase(CIT), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog(KIT), CDC-Like Kinase family-Hepatocyte growth factor receptor (MET),Proto-oncogene tyrosine-protein kinase receptor, colony-stimulatingfactor family receptor, c-src tyrosine kinase (CSK), casein kinasefamily, megakaryocyte-associated tyrosine kinase (CTK), death-associatedprotein kinase family, doublecortin-like kinase family, discoidin domainreceptor tyrosine kinase, dystrophia myotonica-protein kinase (DMPK),dual-specificity tyrosine-(Y)-phosphorylation regulated kinase family,epidermal growth factor receptor family, eukaryotic translationinitiation factor 2-alpha kinase 1 (EIF2AK1), EPH receptor family,Ephrin type-A receptor family, Ephrin type-B receptor family, v-erb-b2erythroblastic leukemia viral oncogene homolog family, mitogen-activatedprotein kinase family, endoplasmic reticulum to nucleus signaling 1(ERN1), PTK2 protein tyrosine kinase 2 (FAK), fer (fps/fes related)tyrosine kinase (FER). feline sarcoma oncogene (FES), Fibroblast growthfactor receptor family, Gardner-Rasheed feline sarcoma viral (v-fgr)oncogene homolog (FGR), fms-related tyrosine kinase family, Fms-relatedtyrosine kinase family, fyn-related kinase (FRK), FYN oncogene relatedto SRC, cyclin G associated kinase (GAK), eukaryotic translationinitiation factor 2 alpha kinase, Growth hormone receptor. Gprotein-coupled receptor kinase 1 (GRK1), G protein-coupled receptorkinase family, glycogen synthase kinase family, germ cell associated 2(haspin) (HASPIN), Hemopoietic cell kinase (HCK), homeodomaininteracting protein kinase family, mitogen-activated protein kinasekinase kinase kinase family, hormonally up-regulated Neu-associatedkinase (HUNK), intestinal cell (MAK-like) kinase (ICK), Insulin-likegrowth factor 1 receptor (IGF1R), conserved helix-loop-helix ubiquitouskinase (IKK-alpha), inhibitor of kappa light polypeptide gene enhancerin B-cells-kinase beta family, insulin receptor (INSR), insulinreceptor-related receptor (INSRR), interleukin-1 receptor-associatedkinase family, IL2-inducible T-cell kinase (ITK), Janus kinase family,Kinase Insert Domain Receptor, v-kit Hardy-Zuckerman 4 feline sarcomaviral oncogene homolog, lymphocyte-specific protein tyrosine kinase(LCK), LIM domain kinase family, serine/threonine kinase familyleucine-rich repeat kinase family, v-yes-1 Yamaguchi sarcoma viralrelated oncogene homolog (LYN), male germ cell-associated kinase (MAK),MAP/microtubule affinity-regulating kinase family, microtubuleassociated serine/threonine kinase family, maternal embryonic leucinezipper kinase, c-mer proto-oncogene tyrosine kinase (MERTK), metproto-oncogene (hepatocyte growth factor receptor), MAP kinaseinteracting serine/threonine kinase family, myosin light chain kinasefamily, mixed lineage kinase domain-like protein isoform, CDC42 bindingprotein kinase family, serine/threonine kinase family, macrophagestimulating 1 receptor (c-met-related tyrosine kinase) (MST1R),mechanistic target of rapamycin (serine/threonine kinase) (MTOR),muscle-skeletal-receptor tyrosine kinase (MUSK), myosin light chainkinase family, NIMA (never in mitosis gene a)-related kinase family,serine/threonine-protein kinase NIM1 (NIM1), nemo-like kinase (NLK),oxidative-stress responsive 1 (OSR1), p21 protein (Cdc42/Rac)-activatedkinase family, PAS domain containing serine/threonine kinase,Platelet-derived growth factor receptor family, 3-phosphoinositidedependent protein kinase-1 (PDPK1), Calcium-dependent protein kinase 1,phosphorylase kinase gamma family, Phosphatidylinositol 4,5-bisphosphate3-kinase, phosphoinositide-3-kinase family, phosphatidylinositol4-kinase family. phosphoinositide kinase, FYVE finger containing, Pim-1oncogene (PIM1), pim-2 oncogene (PIM2), pim-3 oncogene (PIM3),phosphatidylinositol-4-phosphate 5-kinase family,phosphatidylinositol-5-phosphate 4-kinase family protein kinase,membrane associated tyrosine/threonine 1 (PKMYT1), protein kinase Nfamily, polo-like kinase family, protein kinase C family, protein kinaseD family, cGMP-dependent protein kinase family, eukaryotic translationinitiation factor 2-alpha kinase 2 (PRKR), X-linked protein kinase(PRKX), Prolactin receptor (PRLR), PRP4 pre-mRNA processing factor 4homolog B (yeast) (PRP4), PTK2B protein tyrosine kinase 2 beta (PTK2B),SIK family kinase 3 (QSK), v-raf-1 murine leukemia viral oncogenehomolog 1 (RAF1), Neurotrophic tyrosine kinase receptor type family,receptor (TNFRSF)-interacting serine-threonine kinase family, dualserine/threonine and tyrosine protein kinase (RIPK5), Rho-associated,coiled-coil containing protein kinase family, c-ros oncogene 1, receptortyrosine kinase (ROS1), ribosomal protein S6 kinase family, SH3-bindingdomain kinase 1 (SBK1), serum/glucocorticoid regulated kinase family,Putative uncharacterized serine/threonine-protein kinase (Sugen kinase110) (SgK110), salt-inducible kinase family, SNF related kinase (SNRK),src-related kinase, SFRS protein kinase family, Spleen tyrosine kinase(SYK), TAO kinase family, TANK-binding kinase 1 (TBK1), tec proteintyrosine kinase (TEC), testis-specific kinase 1 (TESK1), transforminggrowth factor, beta receptor family, tyrosine kinase withimmunoglobulin-like and EGF-like domains 1 (TIE1), TEK tyrosine kinase,endothelial (TIE2), Angiopoietin-1 receptor (Tie2), tousled-like kinasefamily, TRAF2 and NCK interacting kinase (TNIK), non-receptor tyrosinekinase family, TNNI3 interacting kinase (TNNI3K), transient receptorpotential cation channel, testis-specific serine kinase family, TTKprotein kinase (TTK), TXK tyrosine kinase (TXK), Tyrosine kinase 2(TYK2), TYRO3 protein tyrosine kinase (TYRO3), unc-51-like kinasefamily, phosphatidylinositol 3-kinase, vaccinia related kinase 2 (VRK2),WEE1 homolog family, WNK lysine deficient protein kinase family, v-yes-1Yamaguchi sarcoma viral oncogene homolog 1 (YES), sterile alpha motifand leucine zipper containing kinase AZK (ZAK), zeta-chain (TCR)associated protein kinase 70 kDa (ZAP70); Examples of nuclear hormonereceptors include but are not limited to: Androgen receptor (AR),Estrogen related receptor alpha (ESRRA), Estrogen receptor 1 (ESR1),Nuclear receptor subfamily 1-group H-member 4 (NR1H4), Nuclear receptorsubfamily 3-group C-member 1 (glucocorticoid receptor) (NR3C1), Nuclearreceptor subfamily 1-group H-member 3 (Liver X receptor α) (NR1H3),Nuclear receptor subfamily 1-group H-member 2 (Liver X receptor β)(NR1H2), Nuclear receptor subfamily 1-group H-member 2 (Liver X receptorβ) (NR1H2), Nuclear receptor subfamily 3-group C-member 2(Mineralcorticoid receptor) (NR3C2), Peroxisome Proliferator ActivatedReceptor alpha (PPARA), Peroxisome Proliferator Activated Receptor gamma(PPARG), Peroxisome Proliferator Activated Receptor delta (PPARD),Progesterone receptor α (PGR), Progesterone receptor 13 (PGR), Retinoicacid receptor-alpha (RARA), Retinoic acid receptor-beta (RARB), RetinoidX receptor-alpha (RXRA), Retinoid X receptor-gamma (RXRG), Thyroidhormone receptor-alpha (THRA), Thyroid hormone receptor-beta (THRB),Retinoic acid-related orphan receptor, Liver X receptor, Farnesoid Xreceptor, Vitamin D receptor, Pregnane X receptor, Constitutiveandrostane receptor, Hepatocyte nuclear factor 4, Oestrogen receptor,Oestrogen-related receptor, Glucocortioic receptor, Nerve growthfactor-induced-B, Germ cell nuclear factor; Examples of Epigenetictargets include but are not limited to: ATPase family AAAdomain-containing protein 2 (ATAD2A), ATPase family-AAA domaincontaining 2B (ATAD2B), ATPase family AAA domain containing-2B (ATAD2B),bromodomain adjacent to zinc finger domain-1A (BAZ1A), bromodomainadjacent to zinc finger domain-1B (BAZ1B), bromodomain adjacent to zincfinger domain-2A (BAZ2A), bromodomain adjacent to zinc finger domain-2A(BAZ2A), bromodomain adjacent to zinc finger domain-2B (BAZ2B),bromodomain-containing protein 1 (BRD1), Bromodomain containing protein2-1st bromodomain (BRD2), Bromodomain containing protein 2-1st & 2ndbromodomains (BRD2), bromodomain-containing protein 2 isoform1-bromodomain 2 (BRD2(2)), bromodomain-containing protein 3-bromodomain1 (BRD3(1)), Bromodomain-containing protein 3-1st bromodomain (BRD3),Bromodomain-containing protein 3-1st & 2nd bromodomains (BRD3),bromodomain-containing protein 3-bromodomain 2 (BRD3(2)), Bromodomaincontaining protein 4-1st bromodomain (BRD4), bromodomain-containingprotein 4 isoform long-bromodomains 1 and 2 (BRD4(1-2)),bromodomain-containing protein 4 isoform long-bromodomain 2 (BRD4(2)),bromodomain-containing protein 4 isoform short(BRD4(full-length-short-iso.)), Bromodomain containing protein 7 (BRD7),bromodomain containing 8-bromodomain 1 (BRD8(1)), bromodomain containing8-bromodomain 2 (BRD8(2)), bromodomain-containing protein 9 isoform 1(BRD9), Bromodomain containing testis-specific-1st bromodomain (BRDT),Bromodomain containing testis-specific-1st & 2nd bromodomains (BRDT),bromodomain testis-specific protein isoform b-bromodomain 2 (BRDT(2)),bromodomain and PHD finger containing-1 (BRPF1), bromodomain and PHDfinger containing-3 (BRPF3), bromodomain and PHD finger containing-3(BRPF3), Bromodomain and WD repeat-containing 3-2nd bromodomain(BRWD3(2)), Cat eye syndrome critical region protein 2 (CECR2), CREBbinding protein (CREBBP), E1A binding protein p300 (EP300), EP300(EP300), nucleosome-remodeling factor subunit BPTF isoform 1 (FALZ),Nucleosome-remodeling factor subunit BPT (FALZ), Euchromatichistone-lysine N-methyltransferase 2 (EHMT2), HistoneAcetyltransferase-KAT2A (GCN5L2), Euchromatic histone-lysineN-methyltransferase 1 (EHMT1), Histone-lysine N-methyltransferase MLL(MLL), Polybromo 1-1st bromodomain (PB1(1)), Polybromo 1-2nd bromodomain(PB1(2)), polybromo 1-bromodomain 2 (PBRM1(2)), polybromo 1-bromodomain5 (PBRM1(5)), Histone acetyltransferase KAT2B (PCAF), PH-interactingprotein-1st bromodomain (PHIP(1)), PH-interacting protein-2ndbromodomain (PHIP(2)), Protein kinase C-binding protein 1 (PRKCBP1),Protein arginine N-methyltransferase 3 (PRMT3), SWI/SNF related-matrixassociated-actin dependent regulator of chromatin-subfamily a-member 2(SMARCA2), SWI/SNF related-matrix associated-actin dependent regulatorof chromatin-subfamily a-member 4 (SMARCA4), Nuclear body protein-SP110(SP110), Nuclear body protein-SP140 (SP140), Transcription initiationfactor TFIID subunit 1 (TAF1(1-2)), TAF1 RNA polymerase II-TATA boxbinding protein (TBP)-associated factor-250 kDa-bromodomain 2 (TAF1(2)),Transcription initiation factor TFIID subunit 1-like-1st bromodomain(TAF1L(1)), Transcription initiation factor TFIID subunit 1-like-2ndbromodomain (TAF1 L(2)), tripartite motif containing 24(TRIM24(Bromo.)), tripartite motif containing 24 (TRIM24(PHD-Bromo.)),E3 ubiquitin-protein ligase TRIM33 (TRIM33), tripartite motif containing33 (TRIM33(PHD-Bromo.)), WD repeat 9-1st bromodomain (WDR9(1)), WDrepeat 9-2nd bromodomain (WDR9(2)); membrane transport proteinsincluding but not limited to ATP-binding cassette (ABC) superfamily,solute carrier (SLC) superfamily, multidrug resistance protein 1(P-glycoprotein), organic anion transporter 1, and protein such asEAAT3, EAAC1, EAAT1, GLUT1, GLUT2, GLUT9, GLUT10, rBAT, AE1, NBC1, KNBC,CHED2, BTR1, NABC1, CDPD, SGLT1, SGLT2, NIS, CHT1, NET, DAT, GLYT2,CRTR, BOAT1, SIT1, XT3, y+LAT1, BAT1, NHERF1, NHE6, ASBT, DMT1, DCT1,NRAMP2, NKCC2, NCC, KCC3, NACT, MCT1, MCT8, MCT12, SLD, VGLUT3, THTR1,THTR2, PIT2, GLVR2, OCTN2, URAT1, NCKX1, NCKX5, CIC, PiC, ANT1, ORNT1,AGC1, ARALAR, Citrin, STLN2, aralar2, TPC, MUP1, MCPHA, CACT, GC1, PHC,DTD, CLD, DRA, PDS, Prestin, TAT1, FATP4, ENT3, ZnT2, ZnT10, AT1, NPT2A,NPT2B, HHRH, CST, CDG2F, UGAT, UGTL, UGALT, UGT1, UGT2, FUCT1, CDG2C,NST, PAT2, G6PT1, SPX4, ZIP4, LIV4, ZIP13, LZT-Hs9, FPN1, MTP1, IREG1,RHAG, AIM1, PCFT, FLVCR1, FLVCR2, RFT1, RFT2, RFT3, OATP1B1, OATP1B3,OATP2A1; structural proteins including but not limited to tubulin, heatshock protein, Microtubule-stabilizing proteins, Oncoprotein 18,stathmin, kinesin-8 and kinesin-14 family, Kip3, Kif18A; proteasesincluding but not limited ADAM (a disintegrin and metalloprotease)family; Other molecule targets in signal transductions include but arenot limited to: Cell division cycle 25 homolog A (CDC25A), forkhead boxO3 (forkhead box O3), nuclear factor of kappa light polypeptide geneenhancer in B-cells inhibitor, alpha (NFKBIA), nuclear factor(erythroid-derived 2)-like 2 (NFE2L2), Natriuretic peptide receptor A(NPR1), Tumor necrosis factor receptor superfamily, member 11a(TNFRSF11A), v-rel reticuloendotheliosis viral oncogene homolog A(avian) (RELA), Sterol regulatory element binding transcription factor 2(SREBF2), CREB regulated transcription coactivator 1 (CRTC1), CREBregulated transcription coactivator 2 (CRTC2), X-box binding protein 1(XBP1), Catenin (cadherin-associated protein), beta 1 (CTNNB1), andcombinations thereof.

Examples of known biologics include but are not limited to: Abbosynagis,Abegrin, Actemra, AFP-Cide, Antova, Arzerra, Aurexis, Avastin, Benlysta,Bexxar, Blontress, Bosatria, Campath, CEA-Cide, CEA-Scan, Cimzia,Cyramza, Ektomab, Erbitux, FibriScint, Gazyva, Herceptin, hPAM4-Cide,HumaSPECT, HuMax-CD4, HuMax-EGFr, Humira, HuZAF, Hybri-ceaker, Ilaris,Indimacis-125, Kadcyla, Lemtrada, LeukArrest, LeukoScan, Lucentis,Lymphomun, LymphoScan, LymphoStat-B, MabThera, Mycograb, Mylotarg,Myoscint, NeutroSpec, Numax, Nuvion, Omnitarg, Opdivo, Orthoclone OKT3,OvaRex, Panorex, Prolia, Prostascint, Raptiva, Remicade, Removab,Rencarex, ReoPro, Rexomun, Rituxan, RoActemra, Scintimun, Simponi,Simulect, Soliris, Stelara, Synagis, Tactress, Theracim, Theragyn,Theraloc, Tysabri, Vectibix, Verluma, Xolair, Yervoy, Zenapax, andZevalin or combinations thereof.

Examples of known Monoclonal antibodies include but are not limited to:3F8, 8H9, Abagovomab, Abciximab, Abituzumab, Abrilumab, Actoxumab,Adalimumab, Adecatumumab, Aducanumab, Afasevikumab, Afelimomab,Afutuzumab, Alacizumab pegol, ALD518, ALD403, Alemtuzumab, Alirocumab,Altumomab pentetate, Amatuximab, AMG 334, Anatumomab mafenatox, Anetumabravtansine, Anifrolumab, Anrukinzumab, Apolizumab, Arcitumomab,Ascrinvacumab, Aselizumab, Atezolizumab, Atinumab, Atlizumab,Atorolimumab, Avelumab, Bapineuzumab, Basiliximab, Bavituximab,Bectumomab, Begelomab, Belimumab, Benralizumab, Bertilimumab,Besilesomab, Bevacizumab, Bezlotoxumab, Biciromab, Bimagrumab,Bimekizumab, Bivatuzumab mertansine, Bleselumab, Blinatumomab,Blontuvetmab, Blosozumab, Bococizumab, Brazikumab, Brentuximab vedotin,Briakinumab, Brodalumab, Brolucizumab, Brontictuzumab, Burosumab,Cabiralizumab, Canakinumab, Cantuzumab mertansine, Cantuzumabravtansine, Caplacizumab, Capromab pendetide, Carlumab, Carotuximab,Catumaxomab, cBR96-doxorubicin immunoconjugate, Cedelizumab,Cergutuzumab amunaleukin, Certolizumab pegol, Cetuximab, Citatuzumabbogatox, Cixutumumab, Clazakizumab, Clenoliximab, Clivatuzumabtetraxetan, Codrituzumab, Coltuximab ravtansine, Conatumumab,Concizumab, CR6261, Crenezumab, Crotedumab, Dacetuzumab, Daclizumab,Dalotuzumab, Dapirolizumab pegol, Daratumumab, Dectrekumab, Demcizumab,Denintuzumab mafodotin, Denosumab, Depatuxizumab mafodotin, Derlotuximabbiotin, Detumomab, Dinutuximab, Diridavumab, Domagrozumab, Dorlimomabaritox, Drozitumab, Duligotumab, Dupilumab, Durvalumab, Dusigitumab,Ecromeximab, Eculizumab, Edobacomab, Edrecolomab, Efalizumab, Efungumab,Eldelumab, Elgemtumab, Elotuzumab, Elsilimomab, Emactuzumab,Emibetuzumab, Emicizumab, Enavatuzumab, Enfortumab vedotin, Enlimomabpegol, Enoblituzumab, Enokizumab, Enoticumab, Ensituximab, Epitumomabcituxetan, Epratuzumab, Erenumab, Erlizumab, Ertumaxomab, Etaracizumab,Etrolizumab, Evinacumab, Evolocumab, Exbivirumab, Fanolesomab,Faralimomab, Farletuzumab, Fasinumab, FBTA05, Felvizumab, Fezakinumab,Fibatuzumab, Ficlatuzumab, Figitumumab, Firivumab, Flanvotumab,Fletikumab, Fontolizumab, Foralumab, Foravirumab, Fresolimumab,Fulranumab, Futuximab, Galcanezumab, Galiximab, Ganitumab, Gantenerumab,Gavilimomab, Gemtuzumab ozogamicin, Gevokizumab, Girentuximab,Glembatumumab vedotin, Golimumab, Gomiliximab, Guselkumab, Ibalizumab,Ibritumomab tiuxetan, Icrucumab, Idarucizumab, Igovomab, IMA-638,IMAB362, Imalumab, Imciromab, Imgatuzumab, Inclacumab, Indatuximabravtansine, Indusatumab vedotin, Inebilizumab, Infliximab, Inolimomab,Inotuzumab ozogamicin, Intetumumab, Ipilimumab, Iratumumab, Isatuximab,Itolizumab, Ixekizumab, Keliximab, Labetuzumab, Lambrolizumab,Lampalizumab, Lanadelumab, Landogrozumab, Laprituximab emtansine,LBR-101/PF0442g7429, Lebrikizumab, Lemalesomab, Lendalizumab,Lenzilumab, Lerdelimumab, Lexatumumab, Libivirumab, Lifastuzumabvedotin, Ligelizumab, Lilotomab satetraxetan, Lintuzumab, Lirilumab,Lodelcizumab, Lokivetmab, Lorvotuzumab mertansine, Lucatumumab,Lulizumab pegol, Lumiliximab, Lumretuzumab, LY2951742, Mapatumumab,Margetuximab, Maslimomab, Matuzumab, Mavrilimumab, Mepolizumab,Metelimumab, Milatuzumab, Minretumomab, Mirvetuximab soravtansine,Mitumomab, Mogamulizumab, Monalizumab, Morolimumab, Motavizumab,Moxetumomab pasudotox, Muromonab-CD3, Nacolomab tafenatox, Namilumab,Naptumomab estafenatox, Naratuximab emtansine, Narnatumab, Natalizumab,Navicixizumab, Navivumab, Nebacumab, Necitumumab, Nemolizumab,Nerelimomab, Nesvacumab, Nimotuzumab, Nivolumab, Nofetumomab merpentan,Obiltoxaximab, Obinutuzumab, Ocaratuzumab, Ocrelizumab, Odulimomab,Ofatumumab, Olaratumab, Olokizumab, Omalizumab, Onartuzumab,Ontuxizumab, Opicinumab, Oportuzumab monatox, Oregovomab, Orticumab,Otelixizumab, Otlertuzumab, Oxelumab, Ozanezumab, Ozoralizumab,Pagibaximab, Palivizumab, Pamrevlumab, Panitumumab, Pankomab,Panobacumab, Parsatuzumab, Pascolizumab, Pasotuxizumab, Pateclizumab,Patritumab, Pembrolizumab, Pemtumomab, Perakizumab, Pertuzumab,Pexelizumab, Pidilizumab, Pinatuzumab vedotin, Pintumomab, Placulumab,Plozalizumab, Pogalizumab, Polatuzumab vedotin, Ponezumab, Prezalizumab,Priliximab, Pritoxaximab, Pritumumab, PRO 140, Quilizumab, Racotumomab,Radretumab, Rafivirumab, Ralpancizumab, Ramucirumab, Ranibizumab,Raxibacumab, Refanezumab, Regavirumab, Reslizumab, Rilotumumab,Rinucumab, Risankizumab, Rituximab, Rivabazumab pegol, Robatumumab,Roledumab, Romosozumab, Rontalizumab, Rovalpituzumab tesirine,Rovelizumab, Ruplizumab, Sacituzumab govitecan, Samalizumab,Sapelizumab, Sarilumab, Satumomab pendetide, Secukinumab, Seribantumab,Setoxaximab, Sevirumab, SGN-CD19A, SGN-CD33A, Sibrotuzumab, Sifalimumab,Siltuximab, Simtuzumab, Siplizumab, Sirukumab, Sofituzumab vedotin,Solanezumab, Solitomab, Sonepcizumab, Sontuzumab, Stamulumab, Sulesomab,Suvizumab, Tabalumab, Tacatuzumab tetraxetan, Tadocizumab, Talizumab,Tamtuvetmab, Tanezumab, Taplitumomab paptox, Tarextumab, Tefibazumab,Telimomab aritox, Tenatumomab, Teneliximab, Teplizumab, Teprotumumab,Tesidolumab, Tetulomab, Tezepelumab, TGN1412, Ticilimumab, Tigatuzumab,Tildrakizumab, Timolumab, Tisotumab vedotin, TNX-650, Tocilizumab,Toralizumab, Tosatoxumab, Tositumomab, Tovetumab, Tralokinumab,Trastuzumab, Trastuzumab emtansine, TRBS07, Tregalizumab, Tremelimumab,Trevogrumab, Tucotuzumab celmoleukin, Tuvirumab, Ublituximab,Ulocuplumab, Urelumab, Urtoxazumab, Ustekinumab, Utomilumab,Vadastuximab talirine, Vandortuzumab vedotin, Vantictumab, Vanucizumab,Vapaliximab, Varlilumab, Vatelizumab, Vedolizumab, Veltuzumab,Vepalimomab, Vesencumab, Visilizumab, Vobarilizumab, Volociximab,Vorsetuzumab mafodotin, Votumumab, Xentuzumab, Zalutumumab, Zanolimumab,Zatuximab, Ziralimumab, and Zolimomab aritox or combinations thereof.

Examples of vaccines developed for viral diseases include but are notlimited to: Hepatitis A vaccine, Hepatitis B vaccine, Hepatitis Evaccine, HPV vaccine, Influenza vaccine, Japanese encephalitis vaccine,MMR vaccine, MMRV vaccine, Polio vaccine, Rabies vaccine, Rotavirusvaccine, Varicella vaccine, Shingles vaccine, Smallpox vaccine, YellowFever vaccine, Adenovirus vaccine, Coxsackie B virus vaccine,Cytomegalovirus vaccine, Dengue vaccine for humans, Eastern Equineencephalitis virus vaccine for humans, Ebola vaccine, Enterovirus 71vaccine, Epstein-Barr vaccine, Hepatitis C vaccine, HIV vaccine, HTLV-1T-lymphotropic leukemia vaccine for humans, Marburg virus diseasevaccine, Norovirus vaccine, Respiratory syncytial virus vaccine forhumans, Severe acute respiratory syndrome (SARS) vaccine, West Nilevirus vaccine for humans; Examples of bacterial diseases include but arenot limited to: Anthrax vaccines, DPT vaccine, Q fever vaccine, Hibvaccine, Tuberculosis (BCG) vaccine, Meningococcal vaccine, Typhoidvaccine, Pneumococcal conjugate vaccine, Pneumococcal polysaccharidevaccine, Cholera vaccine, Caries vaccine, Ehrlichiosis vaccine, Leprosyvaccine, Lyme disease vaccine, Staphylococcus aureus vaccine,Streptococcus pyogenes vaccine, Syphilis vaccine, Tularemia vaccine,Yersinia pestis vaccine; Examples of parasitic diseases include but arenot limited to: Malaria vaccine, Schistosomiasis vaccine, Chagas diseasevaccine, Hookworm vaccine, Onchocerciasis river blindness vaccine forhumans, Trypanosomiasis vaccine, Visceral leishmaniasis vaccine;Examples of non-infectious diseases include but are not limited to:Alzheimer's disease amyloid protein vaccine, Breast cancer vaccine,Ovarian cancer vaccine, Prostate cancer vaccine, Talimogenelaherparepvec (T-VEC); also vaccines including but not limited to thefollowing trade names: ACAM2000, ActHIB, Adacel, Afluria, AFLURIAQUADRIVALENT, Agriflu, BCG Vaccine, BEXSERO, Biothrax, Boostrix,Cervarix, Comvax, DAPTACEL, DECAVAC, Engerix-B, FLUAD, Fluarix, FluarixQuadrivalent, Flublok, Flucelvax, Flucelvax Quadrivalent, FluLaval,FluMist, FluMist Quadrivalent, Fluvirin, Fluzone Quadrivalent, Fluzone,Fluzone High-Dose and Fluzone Intradermal, Gardasil, Gardasil 9, Havrix,Hiberix, Imovax, Infanrix, IPOL, Ixiaro, JE-Vax, KINRIX, Menactra,MenHibrix, Menomune-A/C/Y/W-135, Menveo, M-M-R II, M-M-Vax, Pediarix,PedvaxHlB, Pentacel, Pneumovax 23, Poliovax, Prevnar, Prevnar 13,ProQuad, Quadracel, Quadrivalent, RabAvert, Recombivax HB, ROTARIX,RotaTeq, TENIVAC, TICE BCG, Tripedia, TRUMENBA, Twinrix, TYPHIM Vi,VAQTA, Varivax, Vaxchora, Vivotif, YF-Vax, Zostavax, and combinationsthereof.

Examples of injectable drugs include but are not limited to: Ablavar(Gadofosveset Trisodium Injection), Abarelix Depot, Abobotulinumtoxin AInjection (Dysport), ABT-263, ABT-869, ABX-EFG, Accretropin (SomatropinInjection), Acetadote (Acetylcysteine Injection), AcetazolamideInjection (Acetazolamide Injection), Acetylcysteine Injection(Acetadote), Actemra (Tocilizumab Injection), Acthrel (CorticorelinOvine Triflutate for Injection), Actummune, Activase, Acyclovir forInjection (Zovirax Injection), [0137], Adacel, Adalimumab, Adenoscan(Adenosine Injection), Adenosine Injection (Adenoscan), Adrenaclick,AdreView (Iobenguane 1123 Injection for Intravenous Use), Afluria,Ak-Fluor (Fluorescein Injection), Aldurazyme (Laronidase), AlgluceraseInjection (Ceredase), Alkeran Injection (Melphalan Hcl Injection),Allopurinol Sodium for Injection (Aloprim), Aloprim (Allopurinol Sodiumfor Injection), Alprostadil, Alsuma (Sumatriptan Injection), ALTU-238,Amino Acid Injections, Aminosyn, Apidra, Apremilast, Alprostadil DualChamber System for Injection (Caverject Impulse), AMG 009, AMG 076, AMG102, AMG 108, AMG 114, AMG 162, AMG 220, AMG 221, AMG 222, AMG 223, AMG317, AMG 379, AMG 386, AMG 403, AMG 477, AMG 479, AMG 517, AMG 531, AMG557, AMG 623, AMG 655, AMG 706, AMG 714, AMG 745, AMG 785, AMG 811, AMG827, AMG 837, AMG 853, AMG 951, Amiodarone HCl Injection (Amiodarone HClInjection), Amobarbital Sodium Injection (Amytal Sodium), Amytal Sodium(Amobarbital Sodium Injection), Anakinra, Anti-Abeta, Anti-Beta7,Anti-Beta20, Anti-CD4, Anti-CD20, Anti-CD40, Anti-IFNalpha, Anti-IL13,Anti-OX40L, Anti-oxLDS, Anti-NGF, Anti-NRP1, Arixtra, Amphadase(Hyaluronidase Inj), Ammonul (Sodium Phenylacetate and Sodium BenzoateInjection), Anaprox, Anzemet Injection (Dolasetron Mesylate Injection),Apidra (Insulin Glulisine [rDNA origin] Inj), Apomab, Aranesp(darbepoetin alfa), Argatroban (Argatroban Injection), ArginineHydrochloride Injection (R-Gene 10, Aristocort, Aristospan, ArsenicTrioxide Injection (Trisenox), Articane HCl and Epinephrine Injection(Septocaine), Arzerra (Ofatumumab Injection), Asclera (PolidocanolInjection), Ataluren, Ataluren-DMD, Atenolol Inj (Tenormin I.V.Injection), Atracurium Besylate Injection (Atracurium BesylateInjection), Avastin, Azactam Injection (Aztreonam Injection),Azithromycin (Zithromax Injection), Aztreonam Injection (AzactamInjection), Baclofen Injection (Lioresal Intrathecal), BacteriostaticWater (Bacteriostatic Water for Injection), Baclofen Injection (LioresalIntrathecal), Bal in Oil Ampules (Dimercarprol Injection), BayHepB,BayTet, Benadryl, Bendamustine Hydrochloride Injection (Treanda),Benztropine Mesylate Injection (Cogentin), Betamethasone InjectableSuspension (Celestone Soluspan), Bexxar, Bicillin C-R 900/300(Penicillin G Benzathine and Penicillin G Procaine Injection), Blenoxane(Bleomycin Sulfate Injection), Bleomycin Sulfate Injection (Blenoxane),Boniva Injection (Ibandronate Sodium Injection), Botox Cosmetic(OnabotulinumtoxinA for Injection), BR3-FC, Bravelle (UrofollitropinInjection), Bretylium (Bretylium Tosylate Injection), Brevital Sodium(Methohexital Sodium for Injection), Brethine, Briobacept, BTT-1023,Bupivacaine HCl, Byetta, Ca-DTPA (Pentetate Calcium Trisodium Inj),Cabazitaxel Injection (Jevtana), Caffeine Alkaloid (Caffeine and SodiumBenzoate Injection), Calcijex Injection (Calcitrol), Calcitrol (CalcijexInjection), Calcium Chloride (Calcium Chloride Injection 10%), CalciumDisodium Versenate (Edetate Calcium Disodium Injection), Campath(Altemtuzumab), Camptosar Injection (Irinotecan Hydrochloride),Canakinumab Injection (Ilaris), Capastat Sulfate (Capreomycin forInjection), Capreomycin for Injection (Capastat Sulfate), Cardiolite(Prep kit for Technetium Tc99 Sestamibi for Injection), Carticel,Cathflo, Cefazolin and Dextrose for Injection (Cefazolin Injection),Cefepime Hydrochloride, Cefotaxime, Ceftriaxone, Cerezyme, CarnitorInjection, Caverject, Celestone Soluspan, Celsior, Cerebyx (FosphenytoinSodium Injection), Ceredase (Alglucerase Injection), Ceretec (TechnetiumTc99m Exametazime Injection), Certolizumab, CF-101, ChloramphenicolSodium Succinate (Chloramphenicol Sodium Succinate Injection),Chloramphenicol Sodium Succinate Injection (Chloramphenicol SodiumSuccinate), Cholestagel (Colesevelam HCL), Choriogonadotropin AlfaInjection (Ovidrel), Cimzia, Cisplatin (Cisplatin Injection), Clolar(Clofarabine Injection), Clomiphine Citrate, Clonidine Injection(Duraclon), Cogentin (Benztropine Mesylate Injection), ColistimethateInjection (Coly-Mycin M), Coly-Mycin M (Colistimethate Injection),Compath, Conivaptan Hcl Injection (Vaprisol), Conjugated Estrogens forInjection (Premarin Injection), Copaxone, Corticorelin Ovine Triflutatefor Injection (Acthrel), Corvert (Ibutilide Fumarate Injection), Cubicin(Daptomycin Injection), CF-101, Cyanokit (Hydroxocobalamin forInjection), Cytarabine Liposome Injection (DepoCyt), Cyanocobalamin,Cytovene (ganciclovir), D.H.E. 45, Dacetuzumab, Dacogen (DecitabineInjection), Dalteparin, Dantrium IV (Dantrolene Sodium for Injection),Dantrolene Sodium for Injection (Dantrium IV), Daptomycin Injection(Cubicin), Darbepoietin Alfa, DDAVP Injection (Desmopressin AcetateInjection), Decavax, Decitabine Injection (Dacogen), Dehydrated Alcohol(Dehydrated Alcohol Injection), Denosumab Injection (Prolia),Delatestryl, Delestrogen, Delteparin Sodium, Depacon (Valproate SodiumInjection), Depo Medrol (Methylprednisolone Acetate InjectableSuspension), DepoCyt (Cytarabine Liposome Injection), DepoDur (MorphineSulfate XR Liposome Injection), Desmopressin Acetate Injection (DDAVPInjection), Depo-Estradiol, Depo-Provera 104 mg/ml, Depo-Provera 150mg/ml, Depo-Testosterone, Dexrazoxane for Injection, IntravenousInfusion Only (Totect), Dextrose/Electrolytes, Dextrose and SodiumChloride Inj (Dextrose 5% in 0.9% Sodium Chloride), Dextrose, DiazepamInjection (Diazepam Injection), Digoxin Injection (Lanoxin Injection),Dilaudid-HP (Hydromorphone Hydrochloride Injection), DimercarprolInjection (Bal in Oil Ampules), Diphenhydramine Injection (BenadrylInjection), Dipyridamole Injection (Dipyridamole Injection), DMOAD,Docetaxel for Injection (Taxotere), Dolasetron Mesylate Injection(Anzemet Injection), Doribax (Doripenem for Injection), Doripenem forInjection (Doribax), Doxercalciferol Injection (Hectorol Injection),Doxil (Doxorubicin Hcl Liposome Injection), Doxorubicin Hcl LiposomeInjection (Doxil), Duraclon (Clonidine Injection), Duramorph (MorphineInjection), Dysport (Abobotulinumtoxin A Injection), EcallantideInjection (Kalbitor), EC-Naprosyn (naproxen), Edetate Calcium DisodiumInjection (Calcium Disodium Versenate), Edex (Alprostadil forInjection), Engerix, Edrophonium Injection (Enlon), Eliglustat Tartate,Eloxatin (Oxaliplatin Injection), Emend Injection (FosaprepitantDimeglumine Injection), Enalaprilat Injection (Enalaprilat Injection),Enlon (Edrophonium Injection), Enoxaparin Sodium Injection (Lovenox),Eovist (Gadoxetate Disodium Injection), Enbrel (etanercept), Enoxaparin,Epicel, Epinepherine, Epipen, Epipen Jr., Epratuzumab, Erbitux,Ertapenem Injection (Invanz), Erythropoieten, Essential Amino AcidInjection (Nephramine), Estradiol Cypionate, Estradiol Valerate,Etanercept, Exenatide Injection (Byetta), Evlotra, Fabrazyme (Adalsidasebeta), Famotidine Injection, FDG (Fludeoxyglucose F 18 Injection),Feraheme (Ferumoxytol Injection), Feridex I.V. (Ferumoxides InjectableSolution), Fertinex, Ferumoxides Injectable Solution (Feridex I.V.),Ferumoxytol Injection (Feraheme), Flagyl Injection (MetronidazoleInjection), Fluarix, Fludara (Fludarabine Phosphate), Fludeoxyglucose F18 Injection (FDG), Fluorescein Injection (Ak-Fluor), Follistim AQCartridge (Follitropin Beta Injection), Follitropin Alfa Injection(Gonal-f RFF), Follitropin Beta Injection (Follistim AQ Cartridge),Folotyn (Pralatrexate Solution for Intravenous Injection), Fondaparinux,Forteo (Teriparatide (rDNA origin) Injection), Fostamatinib,Fosaprepitant Dimeglumine Injection (Emend Injection), Foscarnet SodiumInjection (Foscavir), Foscavir (Foscarnet Sodium Injection),Fosphenytoin Sodium Injection (Cerebyx), Fospropofol Disodium Injection(Lusedra), Fragmin, Fuzeon (enfuvirtide), GA101, Gadobenate DimeglumineInjection (Multihance), Gadofosveset Trisodium Injection (Ablavar),Gadoteridol Injection Solution (ProHance), Gadoversetamide Injection(OptiMARK), Gadoxetate Disodium Injection (Eovist), Ganirelix (GanirelixAcetate Injection), Gardasil, GC1008, GDFD, Gemtuzumab Ozogamicin forInjection (Mylotarg), Genotropin, Gentamicin Injection, GENZ-112638,Golimumab Injection (Simponi Injection), Gonal-f RFF (Follitropin AlfaInjection), Granisetron Hydrochloride (Kytril Injection), GentamicinSulfate, Glatiramer Acetate, Glucagen, Glucagon, HAE1, Haldol(Haloperidol Injection), Havrix, Hectorol Injection (DoxercalciferolInjection), Hedgehog Pathway Inhibitor, Heparin, Herceptin, hG-CSF,Humalog, Human Growth Hormone, Humatrope, HuMax, Humegon, Humira,Humulin, Ibandronate Sodium Injection (Boniva Injection), IbuprofenLysine Injection (NeoProfen), Ibutilide Fumarate Injection (Corvert),Idamycin PFS (Idarubicin Hydrochloride Injection), IdarubicinHydrochloride Injection (Idamycin PFS), Ilaris (Canakinumab Injection),Imipenem and Cilastatin for Injection (Primaxin I.V.), Imitrex,Incobotulinumtoxin A for Injection (Xeomin), Increlex (Mecasermin [rDNAorigin] Injection), Indocin IV (Indomethacin Inj), Indomethacin Inj(Indocin IV), Infanrix, Innohep, Insulin, Insulin Aspart [rDNA origin]Inj (NovoLog), Insulin Glargine [rDNA origin] Injection (Lantus),Insulin Glulisine [rDNA origin] Inj (Apidra), Interferon alfa-2b,Recombinant for Injection (Intron A), Intron A (Interferon alfa-2b,Recombinant for Injection), Invanz (Ertapenem Injection), InvegaSustenna (Paliperidone Palmitate Extended-Release InjectableSuspension), Invirase (saquinavir mesylate), Iobenguane 1123 Injectionfor Intravenous Use (AdreView), Iopromide Injection (Ultravist),Ioversol Injection (Optiray Injection), Iplex (Mecasermin Rinfabate[rDNA origin] Injection), Iprivask, Irinotecan Hydrochloride (CamptosarInjection), Iron Sucrose Injection (Venofer), Istodax (Romidepsin forInjection), Itraconazole Injection (Sporanox Injection), Jevtana(Cabazitaxel Injection), Jonexa, Kalbitor (Ecallantide Injection), KCLin D5NS (Potassium Chloride in 5% Dextrose and Sodium ChlorideInjection), KCL in D5W, KCL in NS, Kenalog 10 Injection (TriamcinoloneAcetonide Injectable Suspension), Kepivance (Palifermin), KeppraInjection (Levetiracetam), Keratinocyte, KFG, Kinase Inhibitor, Kineret(Anakinra), Kinlytic (Urokinase Injection), Kinrix, Klonopin(clonazepam), Kytril Injection (Granisetron Hydrochloride), lacosamideTablet and Injection (Vimpat), Lactated Ringer's, Lanoxin Injection(Digoxin Injection), Lansoprazole for Injection (Prevacid I.V.), Lantus,Leucovorin Calcium (Leucovorin Calcium Injection), Lente (L), Leptin,Levemir, Leukine Sargramostim, Leuprolide Acetate, Levothyroxine,Levetiracetam (Keppra Injection), Lovenox, Levocarnitine Injection(Carnitor Injection), Lexiscan (Regadenoson Injection), LioresalIntrathecal (Baclofen Injection), Liraglutide [rDNA] Injection(Victoza), Lovenox (Enoxaparin Sodium Injection), Lucentis (RanibizumabInjection), Lumizyme, Lupron (Leuprolide Acetate Injection), Lusedra(Fospropofol Disodium Injection), Maci, Magnesium Sulfate (MagnesiumSulfate Injection), Mannitol Injection (Mannitol IV), Marcaine(Bupivacaine Hydrochloride and Epinephrine Injection), Maxipime(Cefepime Hydrochloride for Injection), MDP Multidose Kit of TechnetiumInjection (Technetium Tc99m Medronate Injection), Mecasermin [rDNAorigin] Injection (Increlex), Mecasermin Rinfabate [rDNA origin]Injection (Iplex), Melphalan Hcl Injection (Alkeran Injection),Methotrexate, Menactra, Menopur (Menotropins Injection), Menotropins forInjection (Repronex), Methohexital Sodium for Injection (BrevitalSodium), Methyldopate Hydrochloride Injection, Solution (MethyldopateHcl), Methylene Blue (Methylene Blue Injection), MethylprednisoloneAcetate Injectable Suspension (Depo Medrol), MetMab, MetoclopramideInjection (Reglan Injection), Metrodin (Urofollitropin for Injection),Metronidazole Injection (Flagyl Injection), Miacalcin, Midazolam(Midazolam Injection), Mimpara (Cinacalet), Minocin Injection(Minocycline Inj), Minocycline Inj (Minocin Injection), Mipomersen,Mitoxantrone for Injection Concentrate (Novantrone), Morphine Injection(Duramorph), Morphine Sulfate XR Liposome Injection (DepoDur), MorrhuateSodium (Morrhuate Sodium Injection), Motesanib, Mozobil (PlerixaforInjection), Multihance (Gadobenate Dimeglumine Injection), MultipleElectrolytes and Dextrose Injection, Multiple Electrolytes Injection,Mylotarg (Gemtuzumab Ozogamicin for Injection), Myozyme (Alglucosidasealfa), Nafcillin Injection (Nafcillin Sodium), Nafcillin Sodium(Nafcillin Injection), Naltrexone XR Inj (Vivitrol), Naprosyn(naproxen), NeoProfen (Ibuprofen Lysine Injection), Nandrol Decanoate,Neostigmine Methylsulfate (Neostigmine Methylsulfate Injection),NEO-GAA, NeoTect (Technetium Tc 99m Depreotide Injection), Nephramine(Essential Amino Acid Injection), Neulasta (pegfilgrastim), Neupogen(Filgrastim), Novolin, Novolog, NeoRecormon, Neutrexin (TrimetrexateGlucuronate Inj), NPH (N), Nexterone (Amiodarone HCl Injection),Norditropin (Somatropin Injection), Normal Saline (Sodium ChlorideInjection), Novantrone (Mitoxantrone for Injection Concentrate), Novolin70/30 Innolet (70% NPH, Human Insulin Isophane Suspension and 30%Regular, Human Insulin Injection), NovoLog (Insulin Aspart [rDNA origin]Inj), Nplate (romiplostim), Nutropin (Somatropin (rDNA origin) for Inj),Nutropin AQ, Nutropin Depot (Somatropin (rDNA origin) for Inj),Octreotide Acetate Injection (Sandostatin LAR), Ocrelizumab, OfatumumabInjection (Arzerra), Olanzapine Extended Release Injectable Suspension(Zyprexa Relprevv), Omnitarg, Omnitrope (Somatropin [rDNA origin]Injection), Ondansetron Hydrochloride Injection (Zofran Injection),OptiMARK (Gadoversetamide Injection), Optiray Injection (IoversolInjection), Orencia, Osmitrol Injection in Aviva (Mannitol Injection inAviva Plastic Vessel 250), Osmitrol Injection in Viaflex (MannitolInjection in Viaflex Plastic Vessel 250), Osteoprotegrin, Ovidrel(Choriogonadotropin Alfa Injection), Oxacillin (Oxacillin forInjection), Oxaliplatin Injection (Eloxatin), Oxytocin Injection(Pitocin), Paliperidone Palmitate Extended-Release Injectable Suspension(Invega Sustenna), Pamidronate Disodium Injection (Pamidronate DisodiumInjection), Panitumumab Injection for Intravenous Use (Vectibix),Papaverine Hydrochloride Injection (Papaverine Injection), PapaverineInjection (Papaverine Hydrochloride Injection), Parathyroid Hormone,Paricalcitol Injection Fliptop Vial (Zemplar Injection), PARP Inhibitor,Pediarix, PEGIntron, Peginterferon, Pegfilgrastim, Penicillin GBenzathine and Penicillin G Procaine, Pentetate Calcium Trisodium Inj(Ca-DTPA), Pentetate Zinc Trisodium Injection (Zn-DTPA), PepcidInjection (Famotidine Injection), Pergonal, Pertuzumab, PhentolamineMesylate (Phentolamine Mesylate for Injection), Physostigmine Salicylate(Physostigmine Salicylate (injection)), Physostigmine Salicylate(injection) (Physostigmine Salicylate), Piperacillin and TazobactamInjection (Zosyn), Pitocin (Oxytocin Injection), Plasma-Lyte 148(Multiple Electrolytes Inj), Plasma-Lyte 56 and Dextrose (MultipleElectrolytes and Dextrose Injection in Viaflex, Plastic Vessel 250),PlasmaLyte, Plerixafor Injection (Mozobil), Polidocanol Injection(Asclera), Potassium Chloride, Pralatrexate Solution for IntravenousInjection (Folotyn), Pramlintide Acetate Injection (Symlin), PremarinInjection (Conjugated Estrogens for Injection), Prep kit for TechnetiumTc99 Sestamibi for Injection (Cardiolite), Prevacid I.V. (Lansoprazolefor Injection), Primaxin I.V. (Imipenem and Cilastatin for Injection),Prochymal, Procrit, Progesterone, ProHance (Gadoteridol InjectionSolution), Prolia (Denosumab Injection), Promethazine HCl Injection(Promethazine Hydrochloride Injection), Propranolol HydrochlorideInjection (Propranolol Hydrochloride Injection), Quinidine GluconateInjection (Quinidine Injection), Quinidine Injection (QuinidineGluconate Injection), R-Gene 10 (Arginine Hydrochloride Injection),Ranibizumab Injection (Lucentis), Ranitidine Hydrochloride Injection(Zantac Injection), Raptiva, Reclast (Zoledronic Acid Injection),Recombivarix HB, Regadenoson Injection (Lexiscan), Reglan Injection(Metoclopramide Injection), Remicade, Renagel, Renvela (SevelamerCarbonate), Repronex (Menotropins for Injection), Retrovir IV(Zidovudine Injection), rhApo2L/TRAIL, Ringer's and 5% DextroseInjection (Ringers in Dextrose), Ringer's Injection (Ringers Injection),Rituxan, Rituximab, Rocephin (ceftriaxone), Rocuronium Bromide Injection(Zemuron), Roferon-A (interferon alfa-2a), Romazicon (flumazenil),Romidepsin for Injection (Istodax), Saizen (Somatropin Injection),Sandostatin LAR (Octreotide Acetate Injection), Sclerostin Ab, Sensipar(cinacalcet), Sensorcaine (Bupivacaine HCl Injections), Septocaine(Articane HCl and Epinephrine Injection), Serostim LQ (Somatropin (rDNAorigin) Injection), Simponi Injection (Golimumab Injection), SodiumAcetate (Sodium Acetate Injection), Sodium Bicarbonate (SodiumBicarbonate 5% Injection), Sodium Lactate (Sodium Lactate Injection inAVIVA), Sodium Phenylacetate and Sodium Benzoate Injection (Ammonul),Somatropin (rDNA origin) for Inj (Nutropin), Sporanox Injection(Itraconazole Injection), Stelara Injection (Ustekinumab), Stemgen,Sufenta (Sufentanil Citrate Injection), Sufentanil Citrate Injection(Sufenta), Sumavel, Sumatriptan Injection (Alsuma), Symlin, Symlin Pen,Systemic Hedgehog Antagonist, Synvisc-One (Hylan G-F 20 SingleIntra-articular Injection), Tarceva, Taxotere (Docetaxel for Injection),Technetium Tc 99m, Telavancin for Injection (Vibativ), TemsirolimusInjection (Torisel), Tenormin I.V. Injection (Atenolol Inj),Teriparatide (rDNA origin) Injection (Forteo), Testosterone Cypionate,Testosterone Enanthate, Testosterone Propionate, Tev-Tropin (Somatropin,rDNA Origin, for Injection), tgAAC94, Thallous Chloride, Theophylline,Thiotepa (Thiotepa Injection), Thymoglobulin (Anti-Thymocyte Globulin(Rabbit), Thyrogen (Thyrotropin Alfa for Injection), TicarcillinDisodium and Clavulanate Potassium Galaxy (Timentin Injection), TiganInjection (Trimethobenzamide Hydrochloride Injectable), TimentinInjection (Ticarcillin Disodium and Clavulanate Potassium Galaxy),TNKase, Tobramycin Injection (Tobramycin Injection), TocilizumabInjection (Actemra), Torisel (Temsirolimus Injection), Totect(Dexrazoxane for Injection, Intravenous Infusion Only), Trastuzumab-DM1,Travasol (Amino Acids (Injection)), Treanda (Bendamustine HydrochlorideInjection), Trelstar (Triptorelin Pamoate for Injectable Suspension),Triamcinolone Acetonide, Triamcinolone Diacetate, TriamcinoloneHexacetonide Injectable Suspension (Aristospan Injection 20 mg),Triesence (Triamcinolone Acetonide Injectable Suspension),Trimethobenzamide Hydrochloride Injectable (Tigan Injection),Trimetrexate Glucuronate Inj (Neutrexin), Triptorelin Pamoate forInjectable Suspension (Trelstar), Twinject, Trivaris (TriamcinoloneAcetonide Injectable Suspension), Trisenox (Arsenic Trioxide Injection),Twinrix, Typhoid Vi, Ultravist (Iopromide Injection), Urofollitropin forInjection (Metrodin), Urokinase Injection (Kinlytic), Ustekinumab(Stelara Injection), Ultralente (U), Valium (diazepam), Valproate SodiumInjection (Depacon), Valtropin (Somatropin Injection), VancomycinHydrochloride (Vancomycin Hydrochloride Injection), VancomycinHydrochloride Injection (Vancomycin Hydrochloride), Vaprisol (ConivaptanHcl Injection), VAQTA, Vasovist (Gadofosveset Trisodium Injection forIntravenous Use), Vectibix (Panitumumab Injection for Intravenous Use),Venofer (Iron Sucrose Injection), Verteporfin Inj (Visudyne), Vibativ(Telavancin for Injection), Victoza (Liraglutide [rDNA] Injection),Vimpat (lacosamide Tablet and Injection), Vinblastine Sulfate(Vinblastine Sulfate Injection), Vincasar PFS (Vincristine SulfateInjection), Victoza, Vincristine Sulfate (Vincristine SulfateInjection), Visudyne (Verteporfin Inj), Vitamin B-12, Vivitrol(Naltrexone XR Inj), Voluven (Hydroxyethyl Starch in Sodium ChlorideInjection), Xeloda, Xenical (orlistat), Xeomin (Incobotulinumtoxin A forInjection), Xolair, Zantac Injection (Ranitidine HydrochlorideInjection), Zemplar Injection (Paricalcitol Injection Fliptop Vial),Zemuron (Rocuronium Bromide Injection), Zenapax (daclizumab), Zevalin,Zidovudine Injection (Retrovir IV), Zithromax Injection (Azithromycin),Zn-DTPA (Pentetate Zinc Trisodium Injection), Zofran Injection(Ondansetron Hydrochloride Injection), Zingo, Zoledronic Acid for Inj(Zometa), Zoledronic Acid Injection (Reclast), Zometa (Zoledronic Acidfor Inj), Zosyn (Piperacillin and Tazobactam Injection), ZyprexaRelprevv (Olanzapine Extended Release Injectable Suspension) and acombination thereof. It is to be appreciated that mutations of any orall of the drugs and biologics (e.g., antibodies, antisense, RNAinterference, gene therapy, primary and embryonic stem cells, andvaccines) set forth above are considered to be within the purview of theinvention.

Test Methods

It should be understood that although certain methods and equipment aredescribed below, other methods or equipment determined suitable by oneof ordinary skill in the art may be alternatively utilized.

Helium Leak

To evaluate the seal of the plunger to the barrel the leak rate ofhelium from the internals of an assembled syringe system to the externalenvironment was performed. This was accomplished by placing a stopperinto a dry bare glass barrel (no lubricant present) and restraining theplunger rod to prevent movement of the stopper during testing. Theinternal volume of the assembled syringe was evacuated through theneedle by use of a vacuum and replaced with a helium atmospherepressurized to approximately 1 psig. The space around the syringe wasmonitored by use of a Gas chromatography/mass spectrometry (GC/MS) tunedfor helium (LACO's TitanTest™ Helium Leak Tester, Salt Lake City, Utah).The area around the syringe was evacuated and analyzed for Heliumconcentration to determine a helium leak rate at 1 minute after heliumdifferential pressure of approximately 15.7 psid was established.

Slide Force

Slide force was measured by filling syringe with 0.96 ml of Water ForInjection (WFI) and inserting stopper using a vent tube stopperinsertion machine. The syringe used was a staked needle design with a 29gauge ½ inch needle. An appropriate plunger rod to match the stopper wasfitted into the assembled syringe system without moving or disturbingthe stopper. The system was placed into a holder on a force displacementanalyzer and the cross head moved at a rate of 25 mm/minute untilcontact was made between the crosshead and the plunger rod proximal end.The test speed of 250 mm/minute was established, after which forcedisplacement data was obtained. The maximum force obtained was recorded.The force displacement instrument used was a TA XT Plus Texture Analyzerwith a TA-270N syringe test fixture (Hamilton, Mass.).

Contact Width

The contact width of the plunger interface with a glass barrel wasmeasured under 30× magnification averaging 3 measurements on each ribusing a Keyence digital micrometer VHX-5000 (Itasca, Ill.).

Barrel ID

The internal diameter of the syringe barrel was measured by use of adigital three point internal micrometer (Mitutoyo series 468, Aurora,Ill.).

Stopper Rib Diameter and Rib Radius

The rib diameter and rib radius of the stopper was measured using anoptical measurement system (Keyence IM 6225, Itasca, Ill.).

EXAMPLES

A series of stoppers was fabricated as described in U.S. Pat. No.8,722,178 to Ashmead, et al. using a halobutyl with an initial modulusof 3.5 MPa. The stoppers were sized for use with a 1 ml long bare glass(not siliconized or otherwise treated) syringe barrel with a nominalinside diameter of 6.35 mm. The stoppers differed in number, shape andsize of the ribs intended to form the seal against the interior of thesyringe barrel. After processing was completed, the stopper was measuredusing non-contact measuring equipment. The average results for eachdesign are reported in Table 1. The stoppers were washed using warmpurified water with a small amount of detergent, then rinsed and driedto remove any residual contamination from fabrication. The stoppers wereinserted into bare glass barrels and tested as described herein. Theresults are reported in Table 2. Rib 1 is the distal end rib andsubsequent ribs count up towards the proximal end.

Example 1 and Example 2 in Tables 1 and 2 are stoppers which meet theintent of this disclosure.

Comparative Example 3 in Tables 1 and 2 is an example of a stopper whichhas good slide force but is insufficient in diameter to achieve therequired seal and is therefore insufficient.

Comparative Example 4 in Tables 1 and 2 is an example of a stopper whichachieves the required seal but has excessive slide force due to a largerthan desired contact between the stopper and the barrel and is thereforeinsufficient.

In the Tables, OD represents outer diameter and ID represents innerdiameter.

TABLE 1 OD Rib 1 OD Rib 2 OD Rib 3 rib 1 radius rib 2 radius rib 3radius Rib 4 OD/rad, Sample (mm) (mm) (mm) (mm) (mm) (mm) Rib 5 OD/radExample 1 7.42 0.12 7.41 0.13 6.73 0.26 Example 2 7.42 0.15 7.41 0.167.40 0.16 Comparative 6.62 0.90 6.62 0.89 6.62 0.89 Example 3Comparative 7.35 0.07 7.27 0.14 7.21 0.16 7.20/0.173, Example 47.23/0.21

TABLE 2 Contact Total Contact He Maximum Barrel Compression width widthleak extrusion ID (Rib 1) rib 1 (ribs with rate (break loose) Sample(mm) (%) (mm) C > 7.9%) (sccs) force (N)) Example 1 6.35 14.42 0.37 0.738.27⁻⁸ 9.8 Example 2 6.35 14.47 0.56 1.62 4.7⁻⁸ 12.5 Comparative 6.354.06 0.52 N/A 1.5⁻⁵ 5.2 example 3 Comparative 6.35 13.61 0.40 1.94 7.7⁻⁸21.8 example 4

The invention of this application has been described above bothgenerically and with regard to specific embodiments. It will be apparentto those skilled in the art that various modifications and variationscan be made in the embodiments without departing from the scope of thedisclosure. Thus, it is intended that the embodiments cover themodifications and variations of this invention provided they come withinthe scope of the appended claims and their equivalents.

1.-9. (canceled)
 10. A medical delivery device comprising: a barrelhaving an inner surface; a plunger rod having a distal end insertedwithin the barrel; a stopper attached to the distal end of the plungerrod and contacting at least a portion of the inner surface of thebarrel, the stopper comprising an elastomeric body, one or morefluoropolymer layers, and two or more ribs having a sealing surface,wherein the one or more fluoropolymer layers is positioned on at leastone of the two or more ribs, and wherein a contact width between atleast one of the two or more ribs and a portion of the inner surface ofthe barrel measured at a compressibility of greater than about 7.9% ofthe stopper is less than about 1.0 mm.
 11. The medical delivery deviceof claim 10, wherein the inner surface is a hydrophilic inner surface.12. The medical delivery device of claim 10, wherein the inner surfaceis free or substantially free of lubricants.
 13. The medical deliverydevice of claim 10, wherein the two or more ribs are laminated with theone or more fluoropolymer layers.
 14. The medical delivery device ofclaim 10, wherein the stopper further comprises a sliding surface thatis less than about 2.0 mm.
 15. The medical delivery device of claim 10,wherein the inner surface is bare glass.
 16. The medical delivery deviceof claim 10, wherein each rib of the two or more ribs having a sealingsurface comprises a radius of curvature at an apex of each respectiverib that is less than about 0.22 mm.
 17. The medical delivery device ofclaim 16, wherein a ratio of a maximum outer diameter of all the ribshaving a sealing surface to an inner diameter of the inner surface ofthe barrel is greater than about 1.08.
 18. The medical delivery deviceof claim 16, wherein a maximum outer diameter of the ribs having asealing surface is greater than about 5.0 mm, an inner diameter of theinner surface of the barrel is between about 4.65 mm and about 11.85 mm,and a ratio of the maximum outer diameter of the ribs having a sealingsurface to an inner diameter of the inner surface of the barrel isgreater than about 1.08.
 19. The medical delivery device of claim 10,wherein the one or more fluoropolymer layers comprise a single layer ofdensified expanded polytetrafluoroethylene.
 20. The medical deliverydevice of claim 10, wherein each rib of the two or more ribs comprises aradius of curvature at an apex of each respective rib of less than about0.22 mm.
 21. The medical delivery device of claim 20, wherein a ratio ofa maximum outer diameter of all the ribs having a sealing surface to aninner diameter of the inner surface of the barrel is greater than about1.08.
 22. The medical delivery device of claim 20, wherein a maximumouter diameter of the ribs having a sealing surface is greater thanabout 5.0 mm, an inner diameter of the inner surface of the barrel isbetween about 4.65 mm and about 11.85 mm, and a ratio of the maximumouter diameter of the ribs having a sealing surface to an inner diameterof the inner surface of the barrel is greater than about 1.08.
 23. Themedical delivery device of claim 10, wherein the one or morefluoropolymer layers comprise a composite fluoropolymer film having abarrier layer and a porous layer, the barrier layer comprising at leastone member selected from densified expanded polytetrafluoroethylene,polytetrafluoroethylene, fluorinated ethylene propylene, polyethylene,polypropylene, polyvinylidene fluoride, polyvinyl fluoride,perfluoropropyl vinyl ether, or a perfluoroalkoxy polymer and copolymersand combinations thereof.
 24. The medical delivery device of claim 10,wherein each rib of the two or more ribs comprises a radius of curvatureat an apex of curvature of each respective rib that is less than about0.22 mm.
 25. The medical delivery device of claim 24, wherein a ratio ofa maximum outer diameter of all the ribs having a sealing surface to aninner diameter of the inner surface of the barrel is greater than about1.08.
 26. The medical delivery device of claim 24, wherein a maximumouter diameter of the ribs having a sealing surface is greater thanabout 5.0 mm, an inner diameter of the inner surface of the barrel isbetween about 4.65 mm and about 11.85 mm, and a ratio of the maximumouter diameter of the ribs having a sealing surface to an inner diameterof the inner surface of the barrel is greater than about 1.08.
 27. Amedical delivery device comprising: a barrel containing at least onetherapeutic; a plunger rod having a distal end inserted within thebarrel; and a stopper attached to the distal end of the plunger rod andcontacting at least a portion of the inner surface of the barrel, thestopper comprising an elastomeric body, one or more fluoropolymerlayers, and two or more ribs having a sealing surface, wherein the oneor more fluoropolymer layers is positioned on at least one of the two ormore ribs, and wherein a contact width between at least one of said twoor more ribs and a portion of the inner surface of the barrel measuredat a compressibility of greater than about 7.9% of the stopper is lessthan about 1.0 mm.
 28. The medical delivery device of claim 27, whereinsaid barrel is a silicone free syringe barrel.
 29. The medical deliverydevice of claim 27, wherein said therapeutic comprises at least onebioactive selected from coagulation factors, cytokines, epigeneticprotein families, growth factors, hormones, peptides, signaltransduction molecules, vaccines, and combinations thereof.
 30. Themedical delivery device of claim 27, wherein said therapeutic comprisesmutations of a bioactive selected from coagulation factors, cytokines,epigenetic protein families, growth factors, hormones, peptides, signaltransduction molecules, vaccines, and combinations thereof.
 31. Themedical delivery device of claim 27, wherein said therapeutic comprisesat least one bioactive selected from protein kinases, esterases,phosphatases, ion channels, proteases, structural proteins, membranetransport proteins, nuclear hormone receptors, and mutations andcombinations thereof.
 32. The medical delivery device of claim 27,wherein said therapeutic comprises at least one bioactive selected fromantibodies, antisense, RNA interference, target receptors, andcombinations thereof.
 33. The medical delivery device of claim 27,wherein said therapeutic comprises at least one bioactive selected fromprimary and embryonic stem cells.
 34. The medical delivery device ofclaim 27, wherein the therapeutic is factor VII.
 35. The medicaldelivery device of claim 27 used for treatment of ocular disease.